(Circulation. 1995;92:2951-2958.)
© 1995 American Heart Association, Inc.
Articles |
Changes in Effective Regurgitant Orifice Throughout Systole in Patients With Mitral Valve Prolapse
A Clinical Study Using the Proximal Isovelocity Surface Area Method
From the Division of Cardiovascular Diseases and Internal Medicine (M.E.-S., L.J.S., A.J.T., J.B.S.) and the Section of Biostatistics (K.R.B.), Mayo Clinic and Mayo Foundation, Rochester, Minn.
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Abstract |
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Background In patients with mitral valve prolapse, spontaneous changes of the effective regurgitant orifice during systole are not well documented. Such changes can now be analyzed by use of the proximal isovelocity surface area method, but the changes raise concern about the reliability of this method for assessing overall severity of regurgitation in these patients.
Methods and Results In a prospective study of 42 patients with mitral valve prolapse, the effective mitral regurgitant orifice was calculated at four phases of systole (early, mid, mid-late, and late) as the ratio of regurgitant flow to regurgitant velocity by use of the proximal isovelocity surface area method. Throughout systole, the effective regurgitant orifice increased significantly, from 32±27 mm2 in early systole to 41±27 in midsystole, 55±30 in mid-late systole, and 107±66 mm2 during late systole (P<.0001). Phasic regurgitant volume increased from early to mid-late systole but decreased in late systole. For quantitation of the overall effective regurgitant orifice, four approaches using the proximal isovelocity surface area were compared with simultaneously performed quantitative Doppler echocardiography (54±30 mm2) and quantitative two-dimensional echocardiography (51±29 mm2). All correlations were good (r>.95), but overestimation was considerable when the largest flow convergence was used (70±39 mm2; both P<.0001), significant when the simple mean of the four phases was used (59±36 mm2; P=.005 and P=.0007, respectively), mild when a weighted mean of the four phases was used (55±33 mm2; P=.41 and P=.01, respectively), and no overestimation was observed when the effective regurgitant orifice calculated at maximum regurgitant velocity was used (54±30 mm2; P=.29 and P=.17, respectively).
Conclusions Phasic changes of mitral regurgitation are observed in patients with mitral valve prolapse. The effective regurgitant orifice increases throughout systole. Regurgitant volume also increases initially but tends to decrease in late systole. These changes can lead to overestimation of the overall degree of regurgitation, but properly timed measurements made by use of the proximal isovelocity surface area method allow an accurate estimation of the overall effective regurgitant orifice.
Key Words: echocardiography • regurgitation • mitral valve • valves
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Introduction |
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In patients with mitral regurgitation, a variation in the degree of regurgitation can be obtained by hemodynamic manipulations.1 2 This variation may affect not only the regurgitant volume but also the regurgitant orifice, as demonstrated clinically in functional regurgitation3 4 5 and experimentally in fixed valvular lesions.6 7 8 Moreover, variability of the area of the effective regurgitant orifice (ERO) throughout each systolic phase of the cardiac cycle has been suggested by a few experimental9 and clinical data.10
Although mitral valve prolapse is a frequent finding,11 12 data on the potential changes of ERO throughout systole are rare10 and difficult to reconcile. In this setting, the usual observation of a late systolic increase in the degree of prolapse,13 14 suggesting a late predominance of regurgitation,10 is at variance15 with the notion that in mitral regurgitation most of the regurgitant volume is ejected early.16 17 It is also at variance with the concept of a parallel decrease in left ventricular volume and regurgitant orifice throughout systole.6 9 Also, late prolapse is concomitant with a decrease in left ventricular pressure or driving force of regurgitation, which represents an additional confounding factor. Hence, to understand the pathophysiology of this type of lesion, it is essential to analyze the phasic variations of the ERO and regurgitant volume during systole in an adequate series of patients with mitral valve prolapse.
Recently, measurement of the instantaneous mitral ERO has become clinically feasible with use of the proximal isovelocity surface area (PISA) method.18 19 This method offers an opportunity to measure instantaneously the regurgitant flow and regurgitant orifice of the mitral valve at specific times during systole. However, a variable ERO would raise concern about the reliability of this instantaneous method for assessing the overall severity of regurgitation throughout systole. This concern was substantiated by our recent observation of a tendency for overestimation of overall ERO by use of PISA in patients with mitral valve prolapse,19 although the impact of potential dynamic changes of ERO10 is unclear.
Therefore, the hypothesis examined in the present study is that in patients with mitral valve prolapse (1) progressive increase, not decrease, in ERO occurs during systole; (2) this variability may lead to overestimation of overall regurgitation by use of the PISA method; but (3) despite this variability, reliable estimates of the overall ERO can be obtained with properly timed PISA measurements.
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Methods |
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Patients were prospectively enrolled into this study in 1993 and 1994. The present study was undertaken as a corollary of the observation in a previous prospective study performed in 1992 and 1993 that overestimation of ERO by use of the PISA method may occur in patients with mitral valve prolapse.19 The inclusion criteria were (1) presence of mitral valve prolapse20 on long-axis echocardiographic views, (2) presence of at least mild holosystolic regurgitation, (3) overall quantitation of mitral regurgitation with use of two simultaneous methods (quantitative Doppler echocardiography and quantitative two-dimensional echocardiography [2DE]), and (4) simultaneous sequential quantitation of mitral regurgitation throughout systole by use of the PISA method, with the requirement that adequate flow convergence19 be present to confirm that accurate regurgitant flow could be measured in all phases of systole. Exclusion criteria were (1) mitral regurgitation limited to a fraction of systole or (2) associated aortic valve disease.
Forty-two patients were included in the study (34 men, 8 women); mean age was 65±14 years. New York Heart Association functional class was class I in 22 patients, class II in 13, class III in 4, and class IV in 3. Of the 42 patients, 38 were in sinus rhythm. Thirty-three patients had a prolapse with a flail leaflet21 and 9 had a prolapse without a flail segment. The prolapse involved the anterior leaflet in 2 patients, the posterior leaflet in 35, and both leaflets in 5. The jet of mitral regurgitation was eccentric in 37 of the 42 patients (88%). Because of limited patient overlap, partial results of some patients have been presented previously.19
PISA Analysis of Phasic
Regurgitation
The systolic phase of the cardiac cycle was
analyzed from the beginning to the end of mitral
regurgitation, as determined with continuous-wave
Doppler echocardiography (duration, 415±45
milliseconds). Systole was then divided into four phases of equal
duration: early systole, midsystole, mid-late systole, and late
systole. For each phase, the time-velocity integral and maximum
velocity were measured with continuous-wave Doppler
echocardiography, and the radius of the flow
convergence region was measured with color-flow imaging technique
(Fig 1
). At least three measurements of each
variable for each phase were performed and averaged. The proper
concomitant timing of the velocity and radius measurements was ensured
by using the ECG and taking into account the delay caused by the
formation of the color-flow image. The range of variation using
this procedure was ±20 milliseconds, as compared with ±5 milliseconds
for color M-mode echocardiography. During the four
phases of systole, quantitation of mitral regurgitation
was performed on the basis of the PISA method by using
two-dimensional color-flow imaging for visualizing the flow
convergence region proximal to the regurgitant orifice. M-mode color
visualization of the flow convergence region was attempted but could
not be performed consistently through the centerline of the
flow convergence and thus was discontinued. The transducer position was
optimized to minimize the angle between the ultrasonic beam and the
flow direction. A high frame rate (usually 25 Hz) was obtained by using
a zoom of the region of interest. The filter setting was set to
optimize visualization of flow convergence. The color baseline was
shifted downward to decrease the color aliasing
velocity.22 The aliasing velocity was 31±12 cm/s. In each
case, the aliasing velocity was carefully chosen to ensure that the
shape of the visualized proximal flow convergence was adequate,
allowing accurate measurement of regurgitant flow at the four
phases.19 However, because only the axial component of
velocity is visualized with color-flow imaging, the visual
appearance of adequate flow convergence is not a hemisphere but a
portion of a sphere.23 The radius of the flow convergence
region (r) measured with color-flow imaging technique was used to
calculate the regurgitant flow for each phase as18
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where Vr is the selected aliasing velocity.
At each phase (early, mid, mid-late, and late), the corresponding regurgitant velocity and the regurgitant time-velocity integral of the mitral regurgitant signal were then incorporated to perform the following calculations for quantitation of regurgitation:
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Measurement of Overall ERO (or Average ERO Throughout
Systole)
PISA Estimates
Four methods were used to estimate overall ERO with PISA:
(1) Estimation using the largest flow convergence:
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(2) Estimation using measurement at maximum regurgitant velocity, where:
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(3) Estimation using the integration of the four phases, where:
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(4) Estimation using the weighted mean of the four phases, where:
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Doppler Echocardiographic Measurements of
Overall ERO
These measurements were used as references for assessing the
overall severity of regurgitation. All patients
underwent a complete 2DE and Doppler ultrasonographic study, as
described previously.24 25
Quantitative Doppler echocardiography. Quantitative Doppler echocardiography was performed as described previously, in particular by using triplicate measurements of each variable and by careful alignment of the Doppler beam with blood flow.26 With pulse-wave Doppler echocardiography, the mitral and aortic stroke volumes were measured. Quantitative measures of regurgitation were calculated as follows: regurgitant volume (Doppler) was calculated as mitral stroke volume minus aortic stroke volume; regurgitant fraction (Doppler) was calculated as regurgitant volume divided by mitral stroke volume.
The overall mitral ERO27 (ERO [Doppler]) was then calculated as regurgitant volume divided by regurgitant time-velocity integral, where the regurgitant time-velocity integral is obtained with continuous-wave Doppler echocardiography of the mitral regurgitant jet.
Quantitative 2DE. Left ventricular volumes were calculated as recommended by the American Society of Echocardiography28 by use of Simpson's rule (method of disks). Left ventricular stroke volume was calculated as the difference between end-diastolic and end-systolic volumes. Quantitative measurements of regurgitation29 were calculated as follows: regurgitant volume (2DE) was calculated as left ventricular stroke volume minus aortic stroke volume; regurgitant fraction (2DE) was calculated as regurgitant volume (2DE) divided by left ventricular stroke volume.
The overall ERO (ERO [2DE]) was calculated as regurgitant volume (2DE) divided by regurgitant time-velocity integral.
Statistics
Quantitative data were summarized by mean±SD. For PISA
measurements, data were summarized within each of the four phases of
systole. Each variable was analyzed for phase effects by a
repeated measures ANOVA. When the ANOVA demonstrated significant phase
differences, paired t tests between successive phases were
used to further delineate the differences. With regard to the overall
ERO, the association between the four PISA methods of estimating
overall ERO and the Doppler and 2DE measurements of ERO was
assessed by simple linear regression. In addition, the methods were
compared for systematic differences by paired t tests and
the method-related differences submitted to analysis, as
per Bland and Altman.30 Finally, to determine whether
patients with simple prolapse and with flail leaflets exhibited
differences in the patterns of variation throughout systole, an ANOVA
with repeated measures was conducted, including the interactions
between flail and time period, and tested. A probability value of .05
or less was considered significant.
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Results |
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Hemodynamic and regurgitant characteristics of the patients are summarized in Table 1
. The average values
are most consistent with severe regurgitation.
However, the large standard deviations underline the wide scattering of
the degree of regurgitation in individual patients,
including moderate as well as severe
regurgitations.
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Physiological Changes in
Regurgitation During Systole
The overall results obtained by use of the PISA method during the
four phases of systole are presented in Table 2.
For all the variables shown in Table 2, the sequential changes were
highly significant overall using ANOVA for repeated measures (all
P<.0001). Also, for each variable, the differences
between the four phases were all significant by paired t
tests (at least P
.05). It should be noted that throughout
systole, the regurgitant orifice increased. This increase was
progressive and not abrupt, but in the late phase a doubling of the
regurgitant orifice area occurred. From early to mid-late systole,
the regurgitant volume increased markedly, not only because of the
increase in the ERO but also because of the marked increase in the
regurgitant time-velocity integral (or regurgitant gradient).
Despite the increase in regurgitant orifice in late systole, the
decrease in regurgitant velocity resulted in a late decrease in
regurgitant volume, which was thus maximum in mid-late systole. The
sequential changes of regurgitant velocity, ERO, and regurgitant volume
in patients without flail leaflets (ANOVA: P=.0001,
P=.0001, and P=.0001, respectively) and in those
with flail leaflets (ANOVA: P=.0001, P=.0001, and
P=.0001, respectively) are shown in Fig 2.
Despite the differences in overall regurgitation
severity, there was no significant difference in the patterns of
sequential changes throughout systole of ERO (P=.17) or
regurgitant volume (P=.85), whether a flail leaflet was
present or absent.
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Estimation of Overall Regurgitation
A scatterplot and regressions between the four methods of
estimating overall ERO using the PISA and two-reference methods are
presented as Figs 3 and 4 and
quality-control plots are presented as Figs 5 and 6.
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Although all correlations showed excellent correlation coefficient values (r >.95) compared with the overall ERO as measured by quantitative Doppler echocardiography (ERO, 54±30 mm2) and by quantitative 2DE (ERO, 51±29 mm2), the PISA method using the largest flow convergence showed a marked overestimation (70±39 mm2, P<.0001; mean difference compared with Doppler and 2DE, 17±13 and 19±14 mm2, respectively). Overestimation was less with the PISA method using the integration of the four phases (59±36 mm2, P=.005 and P=.0007; mean difference of 5±11 and 7±11 mm2 compared with Doppler and 2DE, respectively). Conversely, PISA estimation of overall ERO using the weighted mean of the four phases showed minimal overestimation (55±33 mm2; P=.41 and P=.01 and mean difference of 1±8 and 3±8 mm2 compared with Doppler and 2DE, respectively), and using the measurement at maximum velocity showed no significant overestimation (54±30 mm2, P=.29 and P=.17 and mean difference of -1±5 and 1.2±6 mm2 compared with Doppler echocardiography and 2DE, respectively). Of note, the sum of the regurgitant volume calculated with PISA at the four phases was 84±45 mL compared with the overall calculation of 82±42 mL obtained with quantitative Doppler echocardiography (P=.44; mean difference, 1.4±11 mL) and 79±40 mL obtained with quantitative 2DE (P=.01; mean difference, 5±12 mL).
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Discussion |
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The present study shows that during systole in patients with mitral valve prolapse
1. The ERO changes throughout systole, increasing progressively and more markedly in late systole.
2. The regurgitant volume also increases progressively, but in late systole, a decrease in regurgitant gradient results in a late decrease in regurgitant volume, which is thus maximal close to the maximum velocity of regurgitation.
3. These phasic changes may be responsible for overestimation of overall ERO by the PISA method. However, a reliable estimation of the overall degree of regurgitation can be obtained using properly timed PISA measurements.
ERO Increases During Systole in Mitral Valve Prolapse
The degree of mitral regurgitation, regardless of
the cause, varies under the influence of hemodynamic
manipulations.1 2 More than a decade ago, it was
demonstrated experimentally that this variability is caused not only by
changes in the ventriculoatrial gradient or driving force but also by
dynamic changes in the area of the regurgitant orifice.6 7 8
Later, the observation of induced variations in ERO was confirmed
clinically in patients with functional
regurgitation.4 5 6 Furthermore, a few
experimental observations suggest that the regurgitant orifice
progressively changes spontaneously during systole.9
However, evidence that a variation of the ERO occurs in patients with
organic valvular lesions is scant, especially in cases of
mitral valve prolapse.10
In patients with mitral valve prolapse, the late systolic predominance of the murmur31 and valvular hammocking32 suggest a late predominance of regurgitation. However, these signs usually coexist with holosystolic regurgitation14 and may not reflect the real timing of regurgitation. Also, this late predominance is at variance with previous observations that regurgitant volume16 17 and regurgitant orifice9 in mitral regurgitation reach a maximum in early systole. Nevertheless, recent preliminary observations with the M-mode format of the PISA method tend to substantiate a late maximization of regurgitation, particularly of the ERO.10 By sequentially quantitating regurgitation during systole in a clinically significant number of patients, the present study definitely corroborates the idea that the ERO progressively increases during systole in patients with both simple mitral valve prolapse and flail leaflets. The apparent discrepancy with previous studies that showed early predominance of regurgitation is probably related to the mechanism of regurgitation. These studies were based on fixed defects of leaflets, in which the progressive decrease in ventricular volume during systole leads to a decrease in regurgitant orifice,9 probably through a remodeling of the regurgitant valvular lesion with better coaptation.6 Conversely, in mitral valve prolapse, the systolic decrease in ventricular volume increases the degree of prolapse of leaflets,13 thus increasing the regurgitant orifice. Furthermore, both in simple prolapse and in flail leaflets, the progressive decrease in papillary muscle–annulus distance33 and the incomplete reduction in annulus area34 during systole may contribute to the late systolic increase of ERO.
Nevertheless, the changes in ERO in patients with mitral valve prolapse
do not parallel entirely the changes in regurgitant
volume.15 From early to mid-late systole, the
regurgitant volume increases markedly because of the concomitant
increase in both the ERO and the regurgitant velocity. In late systole,
despite a large increase in regurgitant orifice, the decrease of the
ventriculoatrial gradient demonstrated by the decrease in regurgitant
velocity35 induces a decline in regurgitant volume. Thus,
the regurgitant volume peaks earlier than the ERO, close to the
maximum regurgitant velocity (Fig 2
).
PISA Method
The recently developed PISA method36 uses
color-flow imaging of the flow convergence region37
proximal to the regurgitant lesion to quantitate the
regurgitation.22 This technique is highly
feasible19 and extremely attractive because of the limited
number of measurements that need to be performed to quantitate mitral
regurgitation. It allows a reliable quantitation of
mitral regurgitant volume38 and orifice,18 19
provided that the flow convergence region is
hemispheric,19 as assumed in the calculation. In the
present study, this condition, which is essential for the accuracy
of the method to ensure that the regurgitant flow was measured
correctly, was confirmed for each phase of systole.
The PISA method can provide instantaneous measurement of regurgitant flow at discrete instants in time. By use of the concomitant velocity of regurgitation as measured by continuous-wave Doppler, instantaneous ERO can be calculated. This quantitation of regurgitation at discrete phases of the cardiac cycle allows analysis of phasic variations, as in the present study, and provides information about the dynamic nature of regurgitation not available previously.
However, it is also a potential drawback of the method because it raises the question of how these instantaneous measurements should be used for the quantitation of the overall severity of mitral regurgitation (over the entire cardiac cycle) in patients with mitral valve prolapse. This overall or average ERO area represents the overall lesion severity27 and the integrated burden to the heart and is more relevant for clinical decision making and follow-up of patients than for an isolated instantaneous evaluation of regurgitant orifice. We have previously observed overestimation of ERO by PISA in patients with mitral valve prolapse.19 This observation led us to perform the present study to assess the presence of phasic changes of ERO during systole10 and to determine the method most appropriate for accurately estimating overall ERO with PISA. On the basis of the present demonstration of progressive increase in ERO, the largest (late systolic) ERO does not represent the overall severity of the regurgitation. Furthermore, estimation of ERO based on the combination of the largest flow convergence and maximum velocity (ERO [L]) would be a source of error and of large overestimation. The approach using the arithmetic mean of the ERO at the four phases of systole (ERO [I]) also tended to overestimate regurgitation. The combination of the four phases in a weighted ERO (ERO [W]) is a better alternative. In the future, automated techniques39 40 will probably make such integration easier and more reliable. Currently, the simpler measurement of the ERO at maximum regurgitant velocity is an accurate method of estimating the overall regurgitant orifice in patients with mitral valve prolapse. Thus, in spite of the changes in regurgitant orifice, the PISA method can be used clinically in patients with mitral valve prolapse if properly timed measurements are made.
Limitations of the Study
The PISA method is the only method available for instantaneous
quantitation of regurgitation, but it has some
potential limitations. M-mode color-flow imaging of the flow
convergence region41 provides a high sampling rate and is
theoretically an interesting tool for analyzing sequential changes in
flow40 and regurgitant orifice.10 However, in
our experience with mitral valve prolapse, the movement of the leaflets
and the slight angle of the centerline of the flow convergence
represent major limitations in obtaining proper measurements.
Also, because of the changes observed in regurgitant flow and orifice,
it is essential to confirm that the flow convergence at each phase
complies with the assumption of a hemispheric shape,42 43
which is not possible with the M-mode technique44 and may
introduce considerable error.19 42
The two-dimensional color-flow imaging technique has a lower sampling rate and a slightly higher range of error for the timing of measurements (20 milliseconds versus 5 milliseconds) than does the M-mode technique. However, in all patients, a zoom of the region of interest provided a high frame rate, allowing measurement of flow convergence at the four phases of the cardiac cycle. Multiple measurements limited the potential variations on the timing and values at each phase of systole. The most important advantage of the two-dimensional technique is the confirmation that the flow convergence shape visualized at each phase is adequate. In a wide variety of etiologies and morphologies of the mitral valve, two-dimensional color-flow analysis of the flow convergence region has been validated as accurately measuring the ERO18 19 of mitral regurgitation if adequate flow convergence can be obtained.19 Finally, the consistency of the results obtained with the M-mode technique10 or the present two-dimensional color-analysis technique confirms that, regardless of the technique used, the conclusion that the ERO in mitral valve prolapse is variable and increases progressively throughout systole is valid and should be taken into account in assessing these lesions.
The changing ERO is also a limitation to measuring the phasic regurgitant volume. The phasic calculation is the simplification of what ideally should be an instantaneous integration, which is not possible with current techniques. However, the sum of the phasic regurgitant volumes is not significantly different from the overall regurgitant volume as measured by quantitative Doppler echocardiography and is very close to the results provided by quantitative 2DE, demonstrating that this source of error is minor and that this mode of calculation is acceptable for describing the pattern of variation of the phasic regurgitant volume.
In the present study, the ERO was calculated at times of systole in which regurgitant flow and velocity are both measurable. Although the ERO is null at mitral valve closing and opening, we evidently could not calculate such an orifice and, in the graphs, did not plot a return to the zero line.
With regard to the reference methods used for overall quantitation of regurgitation, the accuracy of quantitative Doppler echocardiography has been questioned,45 but with consistent use, its accuracy has been confirmed in our laboratory.46 The reliability of left ventricular volume measurement using high-resolution imaging has been demonstrated also.47 Moreover, in the present study, the two techniques provided similar results, further confirming that their use is not a limitation.
A selected population of patients with mitral valve prolapse was examined. By including patients with only holosystolic regurgitation, those with regurgitation limited to late systole were excluded, but the progressive nature of regurgitation in those patients is already evident. Also, adequate measurements of PISA had to be obtained during each of the four phases of systole. This criterion excluded from the study patients with major increase of regurgitant orifice and flow in whom the late flow convergence was not adequate at the selected aliasing velocity because of high flow. However, this subset of patients would only reinforce the conclusion of the study; therefore, this criterion is not a limitation to the study. It may be possible to analyze this subset in the future with automated techniques of flow and orifice measurement.
Conclusions
In patients with mitral valve prolapse and
holosystolic regurgitation, the regurgitant
orifice progressively increases throughout systole. The regurgitant
volume also increases initially but tends to decrease in late systole.
These phasic changes can lead to overestimation of the overall
regurgitation by use of the PISA method, but properly
timed measurements allow an accurate estimation of the overall ERO.
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Acknowledgments |
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We appreciate the expert help of Janet L. Halling (secretarial assistance), Sara L. Fett (data analysis), and Ileen C. Marxhausen (data processing).
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Footnotes |
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Reprint requests to Maurice Enriquez-Sarano, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
Received September 22, 1994; revision received April 26, 1995; accepted May 13, 1995.
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