This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by He, S. Articles by Levine, R. A. Search for Related Content PubMed PubMed Citation Articles by He, S. Articles by Levine, R. A.

(Circulation. 1997;96:1826-1834.)
© 1997 American Heart Association, Inc.

Articles

Integrated Mechanism for Functional Mitral Regurgitation

Leaflet Restriction Versus Coapting Force: In Vitro Studies

Shengqiu He, MD; Arnold A. Fontaine, PhD; Ehud Schwammenthal, MD, PhD; Ajit P. Yoganathan, PhD; ; Robert A. Levine, MD

From the Institute for Bioengineering and Bioscience, Chemical Engineering Department, Georgia Institute of Technology, Atlanta (S.H., A.A.F., A.P.Y.), and Massachusetts General Hospital, Boston (E.S., R.A.L.).

Correspondence to Professor Ajit P. Yoganathan, Chemical Engineering Department, Georgia Institute of Technology, 778 Atlantic Dr, Atlanta, GA 30332-0100. E-mail ajit.yoganathan{at}che.gatech.edu

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Functional mitral regurgitation in patients with ischemic or dilated ventricles has been related to competing factors: altered tension on the leaflets due to displacement of their papillary muscle and annular attachments, which restricts leaflet closure, versus global ventricular dysfunction with reduced transmitral pressure to close the leaflets. In vivo, however, geometric changes accompany dysfunction, making it difficult to study these factors independently. Functional mitral regurgitation also paradoxically decreases in midsystole, despite peak transmitral driving pressure, suggesting a change in the force balance acting to create a regurgitant orifice, with rising transmitral pressure counteracting forces that restrict leaflet closure. In vivo, this mechanism cannot be tested independently of annular contraction that could also reduce midsystolic regurgitation.

Methods and Results An in vitro model was developed that allows independent variation of papillary muscle position, annular size, and transmitral pressure, with direct regurgitant flow rate measurement, to test the hypothesis that functional mitral regurgitation reflects an altered balance of forces acting on the leaflets. Hemodynamic and echocardiographic measurements of excised porcine valves were made under physiological pressures and flows. Apical and posterolateral papillary muscle displacement caused decreased leaflet mobility and apical leaflet tethering or tenting with regurgitation, as seen clinically. It reproduced the clinically observed midsystolic decrease in regurgitant flow and orifice area as transmitral pressure increased. Tethering delayed valve closure, increased the early systolic regurgitant volume before complete coaptation, and decreased the duration of coaptation. Annular dilatation increased regurgitation for any papillary muscle position, creating clinically important regurgitation; conversely, increased transmitral pressure decreased regurgitant orifice area for any geometric configuration.

Conclusions The clinically observed tented-leaflet configuration and dynamic regurgitant orifice area variation can be reproduced in vitro by altering the three-dimensional relationship of the annular and papillary muscle attachments of the valve so as to increase leaflet tension. Increased transmitral pressure acting to close the leaflets decreases the regurgitant orifice area. These results are consistent with a mechanism in which an altered balance of tethering versus coapting forces acting on the leaflets creates the regurgitant orifice.

Key Words: mitral valve • echocardiography • regurgitation

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Mitral regurgitation is a common complication in patients with ischemic heart disease or dilated cardiomyopathy, and it influences long-term prognosis and mortality after revascularization.^{1 2 3 4 5 6 7 8 9 10} Although occasional patients have papillary muscle or chordal rupture, patients typically have normal leaflets that are displaced apically relative to their usual position of effective closure at the level of the mitral annulus.^{11 12 13 14 15 16 17 18 19 20 21 22} The precise mechanism of such functional mitral regurgitation remains unclear, with several factors separately proposed that can be grouped under two headings: (1) abnormally increased tension on the leaflets caused by displacement of the papillary muscles or annular dilatation, restricting leaflet motion toward closure,^{11 13 15 17 18 19 20 21} and (2) decreased global left ventricular (LV) systolic function, decreasing the transmitral pressure force acting to close the mitral leaflets,¹⁶ which is the transmitral pressure difference applied over the leaflet cross-sectional area.^{23 24} In vivo, however, it is difficult to study these factors independently: global dysfunction also dilates the ventricle, and acute experimental localized ischemia without global dysfunction may not materially alter the geometry of leaflet attachments.¹⁶

Another aspect of this mechanism for which proposed factors are difficult to separate in vivo is the dynamic behavior of the mitral regurgitant orifice.^{25 26 27 28 29} Recent studies in patients with functional mitral regurgitation have shown that it paradoxically decreases in midsystole even though transmitral pressure is at its peak²⁸ ; this is mediated through a decrease in regurgitant orifice area.^{30 31} This observation could shed light on the mechanism of regurgitation; explanations include a midsystolic decrease in the annular area to be occluded,³² versus increased LV pressure closing the leaflets more effectively. As before, these factors cannot readily be separated in vivo, where mitral regurgitation is also difficult to measure.

The purpose of this study, therefore, was to test the hypothesis that functional mitral regurgitation reflects an altered force balance on the mitral leaflets: a combination of increased tethering forces, restraining the leaflets from closing and resulting from an altered geometry of leaflet attachments (papillary muscles and annulus), and decreased transmitral pressure forces acting to close the valve effectively. This force balance is illustrated in Fig 1. On the one hand, primary changes in the geometry of mitral leaflet attachments should be sufficient to cause apical displacement of the leaflets and mitral regurgitation; despite suggestive evidence, this has not been tested prospectively. On the other hand, when the leaflets are abnormally tethered, mitral regurgitation should decrease with increases in the competing transmitral pressure force generated by LV contraction; this can be tested most clearly in a model that fixes annular size and papillary muscle position, so that variation in regurgitant effective orifice area (EOA) can only relate to varying transmitral pressure. To study these factors separately and in combination, an in vitro model was developed that allows independent variation of papillary muscle position, annular size, and transmitral pressure, as well as direct measurement of regurgitant flow rates. The aim was to increase our understanding of the mechanism of functional mitral regurgitation with the goal of refining practical approaches for reducing its severity.

View larger version (23K): [in this window] [in a new window]   Figure 1. Schematic of force balance on mitral valve leaflets. CT indicates chordae tendineae; MV, mitral valve; and PM, papillary muscle.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Model
Experiments were conducted in the left heart simulator of the Georgia Institute of Technology Cardiovascular Fluid Mechanics Laboratory, which is a computer-controlled, pressure-driven, compressible bladder–type pulsatile pump system.^{33 34} Physiological pulsatile flows can be simulated over a range of conditions from heart rates of 40 to 160 bpm and cardiac outputs up to 10 L/min with physiological pressure and flow waveforms. Throughout the study, a 0.9% (vol/vol) saline solution was used as the blood analogue fluid.

Measurements were conducted in an LV model, shown schematically in Fig 2, providing controlled papillary muscle displacement and mitral annulus dilatation over the range of variation in these parameters seen clinically.^{15 35} This model was designed to simulate the dimensions of the normal human left ventricle at the onset of systole; the positions of the mitral and aortic valves were based on echocardiographic observations of normal human subjects.³⁵ Removable posterior wall segments permitted us to simulate dilatation of the posterior LV wall. An inflow/outflow port located at the model apex and connected to the left heart pulse duplicator provided ventricular filling and emptying during the cardiac cycle. Previous experiments have shown that the flow patterns generated within this LV model are similar to those observed in normal and diseased hearts.³⁴

View larger version (23K): [in this window] [in a new window]   Figure 2. Diagram of in vitro LV model showing mitral valve mounting mechanism consisting of annulus rings and papillary muscle mounting rods.

Valves
Porcine mitral valves with intact chordae tendineae and papillary muscles, with an intertrigonal distance of 25 mm, were tested in the LV model. The mitral valve annulus was mounted to a specially designed model annulus consisting of two rigid rings, shown in Fig 2. The annulus was sutured directly to a physiologically D-shaped inner ring that was attached to a rigid round outer ring by waterproofed Dacron cloth stretched tightly between the two rings. The outer ring was then mounted to the atrial section of the model. This design permitted a wide range of variation in annulus size and shape within an overall diameter of 45 mm.

The anatomic D-shape and size of the inner annulus ring was determined by mitral valve sizers commonly used by surgeons in sizing mitral prosthetic heart valves (Medtronic Heart Valve Inc). The circumference of the normal or baseline annulus ring used in this study was 8.8 cm, comparable to documented normal valves,^{15 32} with a planar area of 6.4 cm². Physiological annular dilatation was simulated by dilating the posterior segment of the inner annulus ring while maintaining the 25-mm intertrigonal distance anteriorly. Dilatation of the posterior annular segment produced a circumference of 11.8 cm, roughly centered on the values reported by Boltwood et al¹⁵ for patients with dilated hearts; this produced a 67% increase in cross-sectional annular area.

The papillary muscles were wrapped in Dacron for support and then sutured to sewing rings on the ends of sigmoidal mounting rods (Fig 2). The mounting mechanism permitted a wide range of papillary muscle motion in the short-axis or lateral plane parallel to the mitral valve annulus and in the apical-to-basal direction, affecting chordal tension. A swivel joint mechanism at the attachment of the sewing rings permitted tilt and rotational freedom of motion of the papillary muscles so that they could come to an equilibrium alignment with the forces exerted through the chordal network.

All porcine mitral valves were slightly fixed in 1% glutaraldehyde solution for 1 minute, then stored and refrigerated in a concentrated antibiotic solution similar to that used to preserve aortic homografts. This procedure prolongs the tissue integrity of the valve and the duration for which it can be tested but limits cross-linking that would adversely affect tissue thickness and stiffness; hemodynamic studies conducted in our laboratory show no measurable effect on valve function. Normal porcine mitral valves were selected because functional regurgitation typically involves incomplete closure of an intrinsically normal valve. Each valve had a total leaflet surface area nearly twice the annulus area, similar to the ratio for normal human valves.³⁶ Kunzelman et al³⁷ found minor geometric differences between the human and porcine mitral valves and identified the porcine valve as an appropriate model for investigation of the human mitral valve system.

Protocol
Five explanted mitral valves were studied under physiological pulsatile flow conditions. Testing was done by systematic variation of annulus size, papillary muscle position, and flow hemodynamics, in that order. First, each valve was sutured to the annulus of normal size. Then the papillary muscles were sequentially studied in one of six positions tested to simulate papillary muscle displacement that may be encountered clinically. For each papillary muscle position, flow and echocardiographic data (described below) were obtained for each of two hemodynamic conditions. Once data were obtained for all six papillary muscle positions and both hemodynamic conditions, the valve was remounted onto the dilated annulus ring, and the protocol was repeated. This resulted in a total of 24 test conditions per valve.

The experiments were conducted with symmetrical displacement of both papillary muscles. Six positions of the papillary muscles were evaluated. Initially, the papillary muscles were placed in a normal position defined by aligning their tips with the coaptation line (Fig 3) and allowing the leaflets to close without regurgitation at the level of the annulus, without prolapse or apical displacement of the leaflets. Next, the papillary muscles were displaced within a short-axis plane parallel to the annulus, first 10 mm away from normal in the lateral direction (away from the center of the valve) and then 10 mm away from normal in the posterolateral direction. Finally, each of these three positions (normal, lateral, and posterolateral) was modified by further displacement in the apical direction by a single increment of 5 to 10 mm to the maximal extent allowed by the leaflet-chordal apparatus. The last three positions are labeled apical, apical and lateral (apical/lateral), and finally apical and posterolateral (apical/posterolateral). These positions were selected to simulate papillary muscle displacement, which can occur in the spectrum of ischemic heart disease or cardiomyopathy.

View larger version (16K): [in this window] [in a new window]   Figure 3. Schematic showing papillary muscle (PM) displacement positions relative to mitral valve annulus. Shape of dilated annulus is also illustrated. Ant. indicates anterior; Pos., posterior; and Leaf., leaflet.

For each annulus size and papillary muscle position, testing was done under two pulsatile flow conditions: (1) cardiac output of 5 L/min, heart rate of 70 bpm, and peak LV pressure of 150 mm Hg, and (2) cardiac output of 3.5 L/min, heart rate of 70 bpm, and peak LV pressure of 90 mm Hg. Systolic duration was fixed at 330 ms.

Observations and Measurements
Regurgitant Volume, Regurgitant Fraction, and Orifice Area
Transmitral pressure differences were directly measured with a differential pressure transducer (model DP15 TL, Validyne Inc) coupled to an amplifier/signal conditioner (model CD12 A-1-A, Validyne Inc). Transmitral forward and regurgitant flow rates were measured by an electromagnetic cannular flow probe (model EP680, Carolina Instruments Inc) with a 2.54-cm internal bore coupled to an analog flowmeter (model FM 501). The transmitral flow rate was measured 2 cm upstream of the valve. All hemodynamic conditions were digitized on a 12-bit PC-based analog-to-digital converter system (Metrabyte DAS-16, Metrabyte Inc). Regurgitant fraction was calculated as regurgitant/transmitral forward flow rates.

Regurgitant effective orifice areas (EOAs) for each valve at each test condition were calculated by two methods: (1) Regurgitant EOA was directly estimated from the measured regurgitant flow rate (Q) and the continuous-wave Doppler regurgitant jet velocity (V) measured from an apical window by use of the continuity equation (EOA=Q/V), when the Doppler beams could be adjusted to record jet velocity measurements with a well-defined envelope, and (2) the modified Bernoulli equation combined with the continuity equation was used to relate regurgitant EOA to transmitral pressure (P) and flow as follows: EOA=Q/[51.6(P)12]. Here, EOA is in units of cm², with pressure and flow measured in units of mm Hg and mL/s, respectively. The instantaneous values of regurgitant EOA were also plotted against time in the pulsatile cycle to determine whether variations in transmitral pressure alone, not annular area, cause EOA to vary.

Because increased leaflet tension with apical displacement of the papillary muscles delayed valve closure, we also measured the early systolic or precoaptation reverse flow volume (the early systolic peak of the regurgitant flow tracing). Even in a normal valve, however, there is a measurable early systolic reverse flow volume that reflects the fluid displaced by the valve during closure; therefore, the precoaptation regurgitant volume was defined as the difference between the measured early systolic closing volume with papillary muscle displacement and the closing volume of the same valve under normal conditions. (This normal early systolic closing volume for the baseline papillary muscle position and annular size was also subtracted from the total regurgitant volume for stages with displacement in each valve.)

Echocardiographic Observations
Two-dimensional (2D) echocardiographic measurements were made with a phased-array ultrasound sector scanner (Sonolayer SSA-270A, Toshiba Inc) at 3.75 MHz, adjusted to provide optimal imaging with the highest possible frame rate at a sampling depth of 15 cm. Five standard 2D echocardiographic views were used: (1) the apical longitudinal views, cutting across both leaflets anteroposteriorly, (2) the apical four-chamber view, (3) and (4) the apical longitudinal views containing the posteromedial and anterolateral papillary muscles, and (5) the short-axis view of the mitral valve.

Echocardiographic data were used to assess mitral valve leaflet function, mobility, and geometry. The following features were measured. (1) As a reflection of the delayed valve closure and premature late-systolic valve opening observed with papillary muscle displacement, the duration of visible leaflet coaptation, referred to as the coaptation time, was measured from the 2D images by use of the frame-by-frame capabilities of the ultrasound machine. Coaptation time was defined as the amount of time for visible coaptation of the mitral valve leaflets at their position of maximal closure achieved at each stage.

The reduced mobility of the leaflets observed with papillary muscle displacement was characterized by three other measures, shown in Fig 4 and measured in the apical longitudinal view: (2) the coaptation length over which the leaflets visibly meet (reduced if they are apically tethered or stretched over a larger annulus); (3) the angle through which the base of the posterior leaflet travels (the posterior leaflet excursion angle, defined as the angle over which the base of the leaflet moves from systole to its fully open diastolic position, measured as the excursion of a tangent line through the base of the leaflet); and (4) the area under the tented leaflets (tented-leaflet area), where leaflet tenting is defined as an apical displacement of the coapted mitral leaflets relative to a line connecting their annular hinge points, with the leaflets taking on a convex curvature relative to the LV apex as opposed to their normal concave configuration.^{13 14 15 16 17 18 19 20 21 22} With regard to the posterior leaflet excursion angle, in the normal papillary muscle position, the base of the posterior leaflet nearly aligns itself with the annular plane during systole and travels through a maximal angle to the fully open position. With increased leaflet tethering due to either papillary muscle displacement or annular dilatation, the base of the posterior leaflet is pulled apically, it is stretched outward as shown in Fig 4, and its range of motion is reduced.

View larger version (20K): [in this window] [in a new window]   Figure 4. Schematic of tented-leaflet geometry. Geometric parameters used to characterize leaflet mobility are illustrated. PM indicates papillary muscle.

Statistics
Standard single-value statistics were computed to 95% confidence intervals. Statistical differences in measures of mitral regurgitation and leaflet mobility with variation of papillary muscle position, annulus size, and peak transmitral pressure were assessed by univariate ANOVA statistics with the general linear model (Minitab, Inc). The five valves were treated as a model factor to reduce the influence of valve-to-valve variability on the statistics for the effects of papillary muscle position, annular size, and transmitral pressure. Significance was assessed for values of P<.05, and the F-test ratio magnitude was used to determine the statistically dominant factors. To discern the influence of papillary muscle short-axis plane position (normal, lateral, and posterolateral), apical displacement, transmitral pressure, and annular dilatation on the measures describing leaflet mobility and regurgitation, main-effects plots³⁸ were also used to describe the dependence of the least-squares mean of the mobility and regurgitation measures on these factors.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Apical Leaflet Tenting and Regurgitation: Observations
Two-dimensional echocardiograms showed complete leaflet coaptation for each valve in the normal papillary muscle position with normal annular size, with no regurgitation. The clinically observed tented-leaflet geometry, illustrated in Fig 4, was successfully reproduced in these in vitro experiments with apical, apical/lateral, and apical/posterolateral displacements of the papillary muscles for both normal and dilated annuli (Fig 5), with associated regurgitation (see below). Lateral and posterolateral papillary muscle displacement without apical displacement produced lesser degrees of leaflet tenting and regurgitation, as quantitatively determined by the ANOVA (see below).

View larger version (81K): [in this window] [in a new window]   Figure 5. Photograph of two-dimensional echo image of a porcine mitral valve with apical/posterolateral papillary muscle displacement and annular dilatation studied under pulsatile flow. Anterior leaflet is tented apically with an immobile, restrained posterior leaflet.

Quantitative Measures
Regurgitant Volume, Regurgitant Fraction, and Orifice Area
Regurgitant fraction increased with both papillary muscle displacement and annular dilatation (Fig 6a). Because of valve-to-valve variability in absolute regurgitant fraction levels, this figure shows the observed trends in regurgitant fraction with variation in the subvalvular assembly and pressure for one valve. These trends were typical of all valves. Regurgitation was greatest with the greatest degree of papillary muscle displacement (apical and posterolateral) and with annular dilatation; smaller increases occurred with lateral or posterolateral papillary muscle shifts but without apical displacement. In addition, for any given papillary muscle position and annular size, regurgitation tended to decrease with increased transmitral pressure, particularly for the stages with the most papillary muscle displacement. The ANOVA-based main effects plot (Fig 6b) illustrates the relative contribution of all these study factors to regurgitant fraction. The horizontal lines represent the data population mean. Papillary muscle displacement, apical tethering, and annular dilatation all significantly affected regurgitant fraction (P<.001). The effect of apical displacement, however, could be discerned from that of papillary muscle displacement in the short-axis plane (normal versus lateral versus posterolateral), as shown in the first two panels of Fig 6b: the F ratio for apical displacement was 112, compared with only 15 for variations in the short-axis position. Annular dilatation was necessary to create more important and clinically significant levels of mitral regurgitation (regurgitant fraction, 20% to 40%). Transmitral pressure also significantly affected regurgitant fraction (P<.01, Fig 6b) but was not the dominant factor. The increase in regurgitant fraction with decreasing transmitral pressure is in part a reflection of the decreased cardiac output at the lower-pressure condition (lower denominator). ANOVA showed no significant difference in total regurgitant volume with transmitral pressure, but this corresponds to a significantly lower regurgitant EOA at the higher pressure, because EOA relates to regurgitant volume/pressure.

View larger version (26K): [in this window] [in a new window]   Figure 6. a, Variation in regurgitant fraction related to papillary muscle (PM) displacement (displ.), annular dilatation, and transmitral pressure (press, pres.). Data represent one valve at all test conditions; trends are representative of all valves. b, ANOVA-determined regurgitant fraction least-squares mean trends as a function of papillary muscle position, apical displacement, transmitral pressure, and annular dilatation for all valves and test conditions. N indicates normal; L, lateral; P/L, posterolateral; T, apically tethered; D, dilated; ann, annulus; Reg., regurgitant; and pos., posterior. ANOVA total mean square error=33.1.

Time course of EOA. In addition to simulating the tented-leaflet geometry seen in patients, the clinically observed early and late systolic peaks in mitral regurgitant flow and EOA²⁸ were reproduced by increased leaflet tethering in this model, with a midsystolic decrease in regurgitant EOA corresponding to rising transmitral pressure. The variations in regurgitant flow rate and EOA with cycle time are illustrated in Fig 7A and 7B for one valve, with a prolonged early systolic maximum of regurgitant EOA related to delayed motion of the leaflets toward closure, as well as a late-systolic peak related to premature opening of the tethered leaflets as the transmitral pressure decreased. With a dilated annulus and apical as well as posterolateral papillary muscle displacement, regurgitant EOA did not return to zero between these peaks, as it did with lesser degrees of leaflet tethering, such as apical displacement with a normal annulus. This time course was observed for each valve. Regurgitant EOA estimated by the continuity and Bernoulli equations compared reasonably well, as illustrated for one of the conditions.

View larger version (18K): [in this window] [in a new window]   Figure 7. Variation of systolic regurgitant flow rate and regurgitant effective orifice area (EOA) for a tented porcine mitral valve. A, Regurgitant flow rate vs systolic time for valve with dilated annulus and apical/posterolateral papillary muscle displacement (large and prolonged early systolic regurgitation, prominent late-systolic peak, and measurable midsystolic regurgitant orifice area). (Early systolic regurgitation at relatively low transmitral pressures reflects unimpeded flow through a valve that is strongly tethered open.) B, Regurgitant EOA vs systolic time. NL (thin line) indicates valve in normal position (small initial closing volume and orifice area); AP (dotted line), apical papillary muscle displacement (small initial closing volume and orifice area with minor late-systolic peak and small midsystolic regurgitant orifice area). AP/PL+ANN (interrupted line and points) indicates apical/posterolateral papillary muscle displacement with dilated annulus. Heavy line shows data from modified Bernoulli equation using catheter-measured pressure; points, data from continuity equation using Doppler velocities.

Precoaptation regurgitant volume. Increasing leaflet tension by apical movement of the papillary muscles delayed valve closure, increasing the early systolic closing volume or precoaptation reverse flow volume above the closing volume measurable with all valves that simply represents the fluid displaced by the valve during closure. The precoaptation regurgitant volume (closing volume with papillary muscle displacement minus closing volume of the same valve under normal conditions) is shown in Fig 8a. Papillary muscle displacement (both posterolateral and apical) and annular dilatation were significant determinants of this precoaptation volume, as illustrated in the main effects plot in Fig 8b, although annular size was the strongest determinant (F ratio of 87).

View larger version (21K): [in this window] [in a new window]   Figure 8. A, Variation in precoaptation regurgitant volume (Pre-Coapt. Reg. Vol.) with papillary muscle (PM) displacement (Displ.), annular dilatation, and transmitral pressure. B, ANOVA-determined precoaptation regurgitant volume least-squares mean trends as a function of papillary muscle short-axis position, apical displacement, transmitral pressure (Pres.), and annular dilatation for all valves and test conditions. Abbreviations as in Fig 6. ANOVA total mean square error=12.1.

Echocardiographic Measures
Coaptation time. Increased tethering of the mitral leaflets produced delayed movement toward closure and premature opening of the leaflets in late systole as the transmitral pressure decreased (Fig 7); this resulted in a correspondingly shorter time during which the mitral leaflets visibly coapted. As shown in Fig 9, there was a strong negative correlation between regurgitant fraction and coaptation time over all conditions of annular size, papillary muscle position, and transmitral pressure.

View larger version (23K): [in this window] [in a new window]   Figure 9. Variation of regurgitant fraction with coaptation time. Data represent all test conditions.

Measures of valve morphology and restricted motion: coaptation length, posterior leaflet excursion angle, and apical tented-leaflet area. The increase in regurgitant fraction resulted from increased leaflet tethering, creating a regurgitant orifice with restricted leaflet mobility. This was reflected in changes in the coaptation length, posterior leaflet excursion angle, and tented area under the leaflets. Apical tethering of the leaflets decreased the length of leaflet coaptation with corresponding increases in regurgitant fraction, as shown in Fig 10. Decreases in the posterior leaflet excursion angle, reflecting decreased leaflet mobility, also correlated with increases in regurgitant fraction (Fig 11); the slope of this relation was steeper for the dilated annulus. Finally, the effect of increased leaflet tethering on the tented area under the leaflets due to papillary muscle displacement and annular dilatation is shown in Fig 12; as for regurgitant fraction, increased transmitral pressure reduced the tented area. Lesser changes (not illustrated) were observed for lateral and posterolateral displacement without apical shifts of the papillary muscles.

View larger version (20K): [in this window] [in a new window]   Figure 10. Variation of regurgitant fraction with coaptation length. Data represent all test conditions.

View larger version (36K): [in this window] [in a new window]   Figure 11. Variation of regurgitant fraction with posterior leaflet excursion angle (mobility). Data represent all test conditions.

View larger version (24K): [in this window] [in a new window]   Figure 12. Variation of tented area with papillary muscle (PM) position, annular dilatation, and transmitral pressure. Data represent one valve at all test conditions. Trends are representative of all valves.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Functional Mitral Regurgitation: Forces Promoting and Opposing Coaptation
The results of this study show that changes in the geometry of the mitral leaflet attachments in a direction that would increase leaflet tension are sufficient to cause functional mitral regurgitation of an initially competent valve in this model. These changes reproduce both the tented-leaflet configuration seen in patients with restricted leaflet motion^{13 14 15 16 17 18 19 20 21 22} and the time course of regurgitant orifice area observed in functional regurgitation.²⁸ Regurgitation occurs with changes at both the papillary muscle and annular ends of the mitral apparatus, consistent with clinical and experimental observations.^{13 14 15 16 17 18 19 20 21 22} On the other hand, although leaflet tethering can produce regurgitation, the data indicate that a competing force also plays a role, namely, the force exerted on the leaflets as a result of the transmitral pressure generated by ventricular contraction.^{16 23 24} In this model, even though papillary muscle and annular geometry are preset in each stage, the regurgitant orifice area varies in the phasic manner seen in patients, reaching a minimum in the midportion of systole, when the transmitral pressure is greatest, and peaking in early and late systole, when tethering forces are least opposed. This effect of transmitral pressure is not surprising because of the geometry of the valve itself, which is constructed so that increased LV pressure will drive the leaflets together to promote an effective seal. This effect of transmitral pressure on regurgitation also becomes more important as the tethering imposed on the leaflets increases (Fig 6a). This emphasizes the competing nature of tethering forces opposing coaptation and transmitral pressure promoting it and supports the hypothesis that functional mitral regurgitation relates to alterations in the force balance acting on the leaflets.

Hypothesis Testing in This Model
Previous in vivo studies of this mechanism have been limited in two ways: first, proposed causes of regurgitation could not be deliberately varied to show that they induced regurgitation in an initially competent valve, and second, competing hemodynamic and geometric explanations could not readily be separated in vivo. For example, Kono and Sabbah et al^{17 18 19 20 21} proposed that regurgitation occurs in more spherical ventricles because of changes in papillary muscle position; this model allows papillary muscle position to be prospectively and directly varied to show that the postulated changes can, in fact, induce regurgitation in this model. The model also allows us to separate the effects of altered geometry from those of global LV dysfunction. Geometric changes could therefore be shown to be sufficient causes of regurgitation in this model despite maintained forward flow and LV pressure. This does not exclude a potential role for severe LV dysfunction in contributing to regurgitation by reducing the transmitral pressure, allowing the tethering forces freer rein. The model design also allowed us to show that phasic changes in transmitral pressure are sufficient to cause variations in regurgitant EOA in this setting. In vivo, of course, annular contraction and expansion also occur³² and may augment these phasic changes in regurgitant EOA, although annular shortening can also be blunted in some patients with ischemic mitral regurgitation.⁶ In summary, therefore, the model allowed us to test potential factors independently, both separately and in combination, to demonstrate how multiple factors can interact in causing regurgitation.³⁹ In addition, regurgitant volume and instantaneous flow rates could be directly measured in this model.

Coaptation Length and Time
Over the entire range of annular, papillary muscle, and hemodynamic variations, there was an inverse correlation between the severity of regurgitation and the coaptation length and time (Figs 9 and 10), which can be viewed as final common pathways for the factors affecting regurgitation. Coaptation time is reduced by the same mechanisms that cause variation in regurgitant EOA: unopposed tethering forces in early and late systole restrict the leaflets from reaching their position of effective coaptation. Coaptation length is reduced by a combination of papillary muscle tethering and annular dilatation, reducing the overlap of the distal leaflets that can be achieved for a given leaflet length. Decreases in coaptation length have similarly been shown to predict increased mitral regurgitation in patients with hypertrophic cardiomyopathy and systolic anterior motion of the mitral valve,⁴⁰ forming a common final mechanism for regurgitation in different settings.

Clinical Correlations, Implications, and Limitations
The results of this study are consistent with previous clinical and experimental observations^{12 13 14 15 16 17 18 19 20 21 28 39 40 41} ; for example, the association between mitral regurgitation and annular dilatation in patients with dilated cardiomyopathy studied by Boltwood et al¹⁵ is consistent with the ability to vary the degree of regurgitation in this model by prospectively increasing annular size, all other factors being held constant. The results are also consistent with the preliminary clinical observation that 14% of 1366 consecutive patients with severely reduced global LV systolic function (mean ejection fraction, 18%) studied by echocardiography had no mitral regurgitation⁴² ; in these patients, regurgitation was strongly related to changes in LV shape and leaflet tethering.^{17 18 19 20 21}

Any clinical implications of this model must be stated circumspectly. Functional mitral regurgitation is not a homogeneous entity. Clearly, a wide spectrum of changes seen clinically can affect the relation of the papillary muscles to the mitral annulus and leaflets, including localized bulging, global sphericity, failure of myocardial contraction, and annular dilatation; these factors can also change within a given patient with revascularization and variations in loading conditions and inotropic state. Nevertheless, interaction among the components of the mitral apparatus must be guided by the basic force balance between the transmitral pressure acting to close the leaflets and the increased tethering forces opposing closure. The in vitro model presented here, by providing independent control of papillary muscle position, annular size, and transmitral pressure and the ability to vary these parameters independently and in combination, allows us to test these interactions and demonstrate the resulting effects and their overall similarity to clinical observations.

This model reproduces the instantaneous papillary muscle and annular relationships that occur with akinetic or dyskinetic function of the posterior left ventricle. Although the dynamic changes of the ventricle as a whole are not reproduced, the pressure and flow changes are. Because it is a feature of ischemic disease to have displacement of the papillary muscles away from the annulus, and especially away and outward in chronic cases with scarring and remodeling of the ventricle, the model does isolate the effect of these typical alterations in papillary muscle position on valvular function. Normally, the mitral apparatus acts as an integrated system, with dynamic changes in both annular size and the relation between the papillary chordal origins and the annulus that permit efficient closure throughout systole.⁶ The model allows us to simulate instantaneous time steps that can reflect the effects of different pathological conditions, for example, posterior wall bulging with papillary muscle displacement or annular dilatation, at different times in the cardiac cycle. Basically, it sheds light on the effects of papillary muscle and annular position at designated points in the cardiac cycle. The concepts and results of these studies can potentially help us gain insight into therapeutic interventions that modify mechanistic factors, for example, the role of annuloplasty (compare the need for annular dilatation in this model to produce clinically important regurgitant fractions),^{5 6 43} the nature of optimal medical therapy (ideally, one that reduces tethering forces and also augments transmitral pressure or at least does not diminish it²⁵ ), and the role of new surgical approaches that can modify geometric relationships, such as papillary muscle repositioning⁶ and resection of posterior wall myocardium between the papillary muscles⁴⁴ in a way that would move them closer together. Ultimately, testing mechanistic factors independently and in a controlled and measurable manner in vivo remains difficult, so the in vitro model provides useful and added information.

Summary
Clinically observed leaflet tenting and the early and late systolic peaks in mitral regurgitant flow and regurgitant EOA were reproduced in this in vitro model by altering the three-dimensional relationship of the annular and papillary muscle attachments of the valve in a manner that would increase leaflet tension. This effect is counteracted by an increase in the transmitral pressure acting to close the leaflets, consistent with the concept that functional mitral regurgitation relates to alterations in the force balance on the leaflets. These alterations in the force balance are reflected in a decreased ability of the mitral valve leaflets to move toward effective coaptation, producing the pattern referred to in patients as incomplete valve closure. Multiple factors can therefore influence different components of this force balance to promote or oppose valve closure; the interaction of these factors can be studied in this in vitro model, which reproduces key features of the clinically observed mitral valve behavior.

	Acknowledgments

 
This work was funded by a grant from the American Heart Association, Georgia Affiliate. We thank Greg Goolsby for his construction of the model and Tina Pennell for her expert editorial assistance.

Received February 3, 1997; revision received May 5, 1997; accepted May 9, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Rankin JS, Hickey MSJ, Smith LR, Muhlbaier L, Reves JG, Pryor DB, Wechsler AS. Ischemic mitral regurgitation. Circulation. 1989;79(suppl I):I-16-I-21.
   
2. Alam M, Thorstrand C, Rosenhamer G. Mitral regurgitation following first-time acute myocardial infarction: early and late findings by Doppler echocardiography. Clin Cardiol. 1993;16:30-34.[Medline] [Order article via Infotrieve]
   
3. Fleischmann KE, Goldman L, Robiollo PA, Lee RT, Johnson PA, Cook EF, Lee TH. Echocardiographic correlates of survival in patients with chest pain. J Am Coll Cardiol. 1994;23:1390-1396.[Abstract]
   
4. Bhatnagar SK, al Yusuf AR. Significance of a mitral regurgitation systolic murmur complicating a first acute myocardial infarction in the coronary care unit: assessment by color Doppler flow imaging. Eur Heart J. 1991;12:1311-1315.[Abstract/Free Full Text]
   
5. Rankin JS, Hickey MJS, Smith LR, DeBruijn NP, Sheikh KH, Sabiston DC Jr. Current concepts in the pathogenesis and treatment of ischemic mitral regurgitation. In: Vetter HO, Hetzer R, Schmutzler H, eds. Ischemic Mitral Incompetence. New York, NY: Springer Verlag; 1991:157-178.
   
6. Frater RWM, Cornelissen P, Sisto D. Mechanisms of ischemic mitral insufficiency and their surgical correction. In: Vetter HO, Hetzer R, Schmutzler H, eds. Ischemic Mitral Incompetence. New York, NY: Springer Verlag; 1991:117-130.
   
7. Barzilai B, Gessler C, Perez J, Schaab C, Jaffe AS. Significance of Doppler-detected mitral regurgitation in acute myocardial infarction. Am J Cardiol. 1988;61:220-223.[Medline] [Order article via Infotrieve]
   
8. Lehmann K, Francis CK, Dodge HT, and the TIMI Study Group. Mitral regurgitation in early myocardial infarction: incidence, clinical detection and prognostic implications. Ann Intern Med. 1992;117:12-17.
   
9. Adler DS, Goldman L, O'Neil A, Cook EF, Mudge GH, Shemin RJ, Disesa V, Cohn LH, Collins JJ. Long-term survival of more than 2000 patients after coronary artery bypass grafting. Am J Cardiol. 1986;58:195-202.[Medline] [Order article via Infotrieve]
   
10. Blondheim DS, Jacobs LE, Kotler MN, Costacurta GA, Parry WR. Dilated cardiomyopathy with mitral regurgitation: decreased survival despite a low frequency of left ventricular thrombus. Am Heart J. 1991;122:763-771.[Medline] [Order article via Infotrieve]
    
11. Burch GE, DePasquale NP, Philips JH. The syndrome of papillary muscle dysfunction. Am Heart J. 1968;75:399-415.[Medline] [Order article via Infotrieve]
    
12. Ogawa S, Hubbard FE, Mardelli TJ, Dreifus LS. Cross-sectional echocardiographic spectrum of papillary muscle dysfunction. Am Heart J. 1979;97:312-321.[Medline] [Order article via Infotrieve]
    
13. Godley RW, Wann SL, Rogers EW, Feigenbaum H, Weyman AE. Incomplete mitral leaflet closure in patients with papillary muscle dysfunction. Circulation. 1981;63:565-571.[Abstract/Free Full Text]
    
14. Izumi S, Miyatake K, Beppu S, Park YD, Nagata S, Kinoshita N, Sakakibara H, Nimura Y. Mechanism of mitral regurgitation in patients with myocardial infarction: a study using real-time two-dimensional Doppler flow imaging and echocardiography. Circulation. 1987;76:777-785.[Abstract/Free Full Text]
    
15. Boltwood CM, Tei C, Wong M, Shah PM. Quantitative echocardiography of the mitral complex in dilated cardiomyopathy: the mechanism of functional mitral regurgitation. Circulation. 1983;68:498-508.[Free Full Text]
    
16. Kaul S, Spotnitz WD, Glasheen WP, Touchstone DA. Mechanism of ischemic mitral regurgitation: an experimental evaluation. Circulation. 1992;84:2167-2180.[Abstract/Free Full Text]
    
17. Kono T, Sabbah HN, Rosman H, Alam M, Jafri S, Stein PD, Goldstein S. Mechanism of functional mitral regurgitation during acute myocardial ischemia. J Am Coll Cardiol. 1992;19:1101-1105.[Abstract]
    
18. Kono T, Sabbah H, Stein PD, Brymer JF, Khaja F. Left ventricular shape as a determinant of functional mitral regurgitation in patients with severe heart failure secondary to either coronary artery disease or idiopathic dilated cardiomyopathy. Am J Cardiol. 1991;68:355-359.[Medline] [Order article via Infotrieve]
    
19. Sabbah H, Kono T, Rosman H, Jafri S, Stein PD, Goldstein S. Left ventricular shape: a factor in the etiology of functional mitral regurgitation in heart failure. Am Heart J. 1992;123:961-966.[Medline] [Order article via Infotrieve]
    
20. Kono T, Sabbah HN, Rosman H, Alam M, Jafri S, Stein PD, Goldstein S. Left ventricular shape is the primary determinant of functional mitral regurgitation in heart failure. J Am Coll Cardiol. 1992;20:1594-1598.[Abstract]
    
21. Sabbah HN, Kono T, Stein PD, Mancini GBJ, Goldstein S. Left ventricular shape changes during the course of evolving heart failure. Am J Physiol. 1992;263:H266-H270.[Abstract/Free Full Text]
    
22. Kisanuki A, Otsuji Y, Kuroiwa R, Murayama T, Matsushita R, Shibata K, Yutsudo T, Nakao S, Nomoto K, Tomari T, Tanaka H. Two-dimensional echocardiographic assessment of papillary muscle contractility in patients with prior myocardial infarction. J Am Coll Cardiol. 1993;21:932-938.[Abstract]
    
23. Burch GE, DePasquale NP. Time course of tension in papillary muscle of heart. JAMA. 1965;192:117-120.
    
24. Arts T, Meerbaum S, Reneman R, Corday E. Stresses in the closed mitral valve: a model study. J Biomech. 1983;16:539-547.[Medline] [Order article via Infotrieve]
    
25. Borgenhagen DM, Serur JR, Gorlin R, Adams D, Sonnenblick EH. The effects of ventricular load and contractility on mitral regurgitant orifice size and flow in the dog. Circulation. 1977;56:106-133.[Abstract/Free Full Text]
    
26. Yoran C, Yellin EL, Becker RM, Gabbay S, Frater RWM, Sonnenblick EH. Dynamic aspects of acute mitral regurgitation: effects of ventricular volume, pressure, and contractility on the effective regurgitant orifice area. Circulation. 1979;60:170-176.[Abstract]
    
27. Yellin EL, Yoran C, Sonnenblick EH, Gabbay S, Frater RWM. Dynamic changes in the canine mitral regurgitant orifice area during ventricular ejection. Circ Res. 1979;45:677-683.[Abstract/Free Full Text]
    
28. Schwammenthal E, Chen C, Benning F, Block M, Breithardt G, Levine R. Dynamics of mitral regurgitant flow and orifice area: physiologic application of the proximal flow convergence method: clinical data and experimental testing. Circulation. 1994;90:307-322.[Abstract/Free Full Text]
    
29. Enriquez-Sarano M, Miller FA, Hayes SN, Bailey KR, Tajik AJ, Seward JB. Effective mitral regurgitant orifice area: clinical use and pitfalls of the proximal isovelocity surface area method. J Am Coll Cardiol. 1995;25:703-709.[Abstract]
    
30. Gorlin R, Dexter L. Hydraulic formula for the calculation of the cross sectional area of the mitral valve during regurgitation. Am Heart J. 1952;43:188-205.[Medline] [Order article via Infotrieve]
    
31. Enriquez-Sarano M, Seward JB, Bailey KR, Tajik AJ. Effective regurgitant orifice area: a noninvasive Doppler development of an old hemodynamic concept. J Am Coll Cardiol. 1994;23:443-451.[Abstract]
    
32. Ormiston JA, Shah PM, Tei C, Wong M. Size and motion of the mitral valve annulus in man, I: a two-dimensional echocardiographic method and findings in normal subjects. Circulation. 1981;64:113-120.[Abstract/Free Full Text]
    
33. Lefebvre XP, He S, Levine RA, Yoganathan AP. Systolic anterior motion of the mitral valve in hypertrophic cardiomyopathy: an in vitro pulsatile flow study. J Heart Valve Dis. 1995;4:422-438.[Medline] [Order article via Infotrieve]
    
34. Fontaine AA, He S, Stadter R, Ellis JT, Levine RA, Yoganathan AP. In vitro assessment of prosthetic valve function in mitral valve replacement with chordae preservation techniques. J Heart Valve Dis. 1996;5:186-198.[Medline] [Order article via Infotrieve]
    
35. Jiang L, Levine RA, King ME, Weyman AE. An integrated mechanism for systolic anterior motion of the mitral valve in hypertrophic cardiomyopathy based on echocardiographic observations. Am Heart J. 1987;113:633-644.[Medline] [Order article via Infotrieve]
    
36. Brock RC. The surgical and pathologic anatomy of the mitral valve. Br Heart J. 1952;14:489-513.
    
37. Kunzelman KS, Cochran RP, Verrier ED, Eberhart RC. Anatomic basis for mitral valve modelling. J Heart Valve Dis. 1994;3:491-496.[Medline] [Order article via Infotrieve]
    
38. Montgomery DC. Design and Analysis of Experiments. 3rd ed. New York, NY: John Wiley & Sons Inc; 1991:chap 7.
    
39. Gorman RC, McCaughan JS, Ratcliffe MB, Gupta KB, Streicher JT, Ferrari VA, St John-Sutton MG, Bogen DK, Edmunds LH Jr. Pathogenesis of acute ischemic mitral regurgitation in three dimensions. J Thorac Cardiovasc Surg. 1995;109:684-693.[Abstract/Free Full Text]
    
40. Schwammenthal E, Nakatani S, He S, Hopmeyer J, Lever HM, Yoganathan AP, Weyman AE, Thomas JD, Levine RA. Mechanism of mitral regurgitation in hypertrophic cardiomyopathy: clinical and experimental findings. J Am Soc Echocardiogr. 1994;7(3 pt 2):S9. Abstract.
    
41. Komeda M, Glasson JR, MacIsaac A, Bolger AF, Osterle SN, Niczyporuk MA, Daughters GT, Ingels NB Jr, Miller DC. Circumflex coronary artery occlusion produces incomplete mitral leaflet closure of the anterior-lateral commissure in intact dogs. Circulation. 1995;92(suppl I):I-356. Abstract.
    
42. Gilon D, Lee M-Y, Jiang L, Otsuji Y, Karvounis H, Roy MJ, Weyman AE, Levine RA. Absence of functional mitral regurgitation (MR) despite severely reduced left ventricle function: insights into the mechanism of MR. J Am Coll Cardiol. 1996;27:115A. Abstract.
    
43. David TE. Techniques and results of mitral valve repair for ischemic mitral regurgitation. J Card Surg. 1994;9(suppl):274-277.
    
44. Bellotti G, Moraes A, Bochi E, Medeiros C, Bacal F, Esteves A, Graziosi P, Moreira LF, Cerri GG, Stolf NG. Surgical remodeling of the left ventricle in severe dilated cardiomyopathy: short-term results on cardiac mechanics. Circulation. 1996;94(suppl I):1-548. Abstract.
    

This article has been cited by other articles:

				J. Hung, J. Solis, J. L. Guerrero, G. J.C. Braithwaite, O. K. Muratoglu, M. Chaput, L. Fernandez-Friera, M. D. Handschumacher, V. J. Wedeen, S. Houser, et al. A Novel Approach for Reducing Ischemic Mitral Regurgitation by Injection of a Polymer to Reverse Remodel and Reposition Displaced Papillary Muscles Circulation, September 30, 2008; 118(14_suppl_1): S263 - S269. [Abstract] [Full Text] [PDF]

				L. D. Gillam Is It Time to Update the Definition of Functional Mitral Regurgitation?: Structural Changes in the Mitral Leaflets With Left Ventricular Dysfunction Circulation, August 19, 2008; 118(8): 797 - 799. [Full Text] [PDF]

				M. Chaput, M. D. Handschumacher, F. Tournoux, L. Hua, J. L. Guerrero, G. J. Vlahakes, and R. A. Levine Mitral Leaflet Adaptation to Ventricular Remodeling: Occurrence and Adequacy in Patients With Functional Mitral Regurgitation Circulation, August 19, 2008; 118(8): 845 - 852. [Abstract] [Full Text] [PDF]

				T. A. Armen, R. Vandse, J. A. Crestanello, S. V. Raman, K. M. Bickle, and N. S. Nathan Mechanisms of valve competency after mitral valve annuloplasty for ischaemic mitral regurgitation using the Geoform ring: insights from three-dimensional echocardiography Eur J Echocardiogr, May 13, 2008; (2008) jen165v1. [Abstract] [Full Text] [PDF]

				E. Agricola, M. Oppizzi, M. Pisani, A. Meris, F. Maisano, and A. Margonato Ischemic mitral regurgitation: mechanisms and echocardiographic classification Eur J Echocardiogr, March 1, 2008; 9(2): 207 - 221. [Abstract] [Full Text] [PDF]

				W. Bothe, T. C. Nguyen, D. B. Ennis, A. Itoh, C. J. Carlhall, D. T. Lai, N. B. Ingels, and D. C. Miller Effects of acute ischemic mitral regurgitation on three-dimensional mitral leaflet edge geometry Eur. J. Cardiothorac. Surg., February 1, 2008; 33(2): 191 - 197. [Abstract] [Full Text] [PDF]

				W. Y. Szeto, R. C. Gorman, J. H. Gorman III, and M. A. Acker Ischemic Mitral Regurgitation Card. Surg. Adult, January 1, 2008; 3(2008): 785 - 802. [Full Text]

				P. Lancellotti, E. Donal, B. Cosyns, G. Van Camp, J.-L. Monin, E. Brochet, A. Berrebi, P. Pibarot, C. Chauvel, C. Hassager, et al. Effects of surgery on ischaemic mitral regurgitation: a prospective multicentre registry (SIMRAM registry) Eur J Echocardiogr, January 1, 2008; 9(1): 26 - 30. [Abstract] [Full Text] [PDF]