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Reproducibility of Proximal Isovelocity Surface Area, Vena Contracta, and Regurgitant Jet Area for Assessment of Mitral Regurgitation Severity

Simon Biner, MD^_*,, Asim Rafique, MD, Farhad Rafii, MD, Kirsten Tolstrup, MD, Omid Noorani, MS, Takahiro Shiota, MD, Swaminatha Gurudevan, MD, Robert J. Siegel, MD^,_*

^_* Division of Cardiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
Division of Cardiology, Cedars-Sinai Medical Center, University of California, Los Angeles, Los Angeles, California
Department of Internal Medicine, Kaiser Permanente, University of California, Los Angeles, Los Angeles, California
Department of Biomathematics, University of California, Los Angeles, Los Angeles, California

	Abstract

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Objectives: The aim of this study was to evaluate the interobserver agreement of proximal isovelocity surface area (PISA) and vena contracta (VC) for differentiating severe from nonsevere mitral regurgitation (MR).

Background: Recommendation for MR evaluation stresses the importance of VC width and effective regurgitant orifice area by PISA measurements. Reliable and accurate assessment of MR is important for clinical decision making regarding corrective surgery. We hypothesize that color Doppler-based quantitative measurements for classifying MR as severe versus nonsevere may be particularly susceptible to interobserver agreement.

Methods: The PISA and VC measurements of 16 patients with MR were interpreted by 18 echocardiologists from 11 academic institutions. In addition, we obtained quantitative assessment of MR based on color flow Doppler jet area.

Results: The overall interobserver agreement for grading MR as severe or nonsevere using qualitative and quantitative parameters was similar and suboptimal: 0.32 (95% confidence interval [CI]: 0.1 to 0.52) for jet area–based MR grade, 0.28 (95% CI: 0.11 to 0.45) for VC measurements, and 0.37 (95% CI: 0.16 to 0.58) for PISA measurements. Significant univariate predictors of substantial interobserver agreement for: 1) jet area–based MR grade was functional etiology (p = 0.039); 2) VC was central MR (p = 0.013) and identifiable effective regurgitant orifice (p = 0.049); and 3) PISA was presence of a central MR jet (p = 0.003), fixed proximal flow convergence (p = 0.025), and functional etiology (p = 0.049). Significant multivariate predictors of raw interobserver agreement 80% included: 1) for VC, identifiable effective regurgitant orifice (p = 0.035); and 2) for PISA, central regurgitant jet (p = 0.02).

Conclusions: The VC and PISA measurements for distinction of severe versus nonsevere MR are only modestly reliable and associated with suboptimal interobserver agreement. The presence of an identifiable effective regurgitant orifice improves reproducibility of VC and a central regurgitant jet predicts substantial agreement among multiple observers of PISA assessment.

Key Words: mitral valve • regurgitation • echocardiography

Abbreviations and Acronyms   CFD = color flow Doppler   EROA = effective regurgitant orifice area   MR = mitral regurgitation   PISA = proximal isovelocity surface area   VC = vena contracta

Visualization of the regurgitant jet area in the left atrium provides a fast assessment of the shape, size, and direction of the regurgitant jet and a qualitative evaluation of its severity, whereas assessment of VC and PISA requires meticulous attention to technical details both at image acquisition and during actual measurements (Figs. 1A and 1B) (2–5). Echocardiographic research laboratories have demonstrated that PISA and VC are accurate for MR assessment and have good interobserver agreement (3,6–11). However, the etiology of MR, the mitral valve morphology, and the regurgitant jet characteristics further complicate the assessment of MR (2,5,6). In addition, the dynamic nature of MR and pansystolic changes in VC and proximal flow convergence rate may also lead to a considerable temporal variation of both the VC width and the 2-dimensional PISA radius throughout systole, causing uncertainty among echocardiogram readers about which particular frame to choose for measurement (7). Therefore, we hypothesized that quantitative measurements of PISA and VC for classifying MR as severe versus nonsevere will have considerable interobserver agreement among clinical echocardiologists.

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Figure 1 Measurement of MR PISA Radius and VC Width (A) A magnified 4-chamber view was used to measure proximal isovelocity surface area (PISA) radius. The Nyquist limit was adjusted in each case to provide optimal visualization of the mitral regurgitation (MR) proximal flow convergence. The PISA radius is measured between the aliasing line of the isovelocity surface and the level of mitral regurgitant orifice. (B) A magnified parasternal long axis view was used to measure vena contracta (VC) width. To obtain an optimal VC, the transducer was sometimes angulated out of the standard imaging plane so as to identify simultaneously the 3 components including: the area of proximal flow acceleration, the VC, and the downstream expansion of the mitral regurgitation jet. The VC width (effective regurgitant orifice) is the dimension of the neck between proximal flow convergence and flow expansion in receiving chamber.

	Methods

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Patients.   Interobserver agreement of jet area–based assessment of MR severity, PISA, and VC was evaluated using transthoracic echocardiograms of 16 consecutive patients referred to Cedars Sinai Medical Center for possible surgical correction of MR. All patients had a history of effort intolerance or were asymptomatic with left ventricular systolic dysfunction. The focus of the assessment was the classification of MR into severe versus nonsevere categories to identify appropriate candidates for mitral valve surgery. The Cedars Sinai Medical Center Institutional Review Board approved this study.

Interpreters.   Eighteen cardiologists with mean 16 (range 2 to 40) years of post-cardiology fellowship experience as echocardiographic specialists (echocardiologists), practicing at 11 different university-based institutions in the U.S., Japan, and Israel were provided secure Web-based access to relevant echocardiographic images. The influence of institutional standards on interobserver agreement was evaluated by comparing the agreement of the 6 echocardiologists practicing in a single institution to the agreement of the echocardiologists from multiple institutions.

Echocardiography.   A single trained sonographer with clinical trial research experience performed all studies. A narrow color flow sector width and the least depth were chosen to maximize image resolution. The CFD images of the mitral valve regurgitant jet were acquired in the parasternal long axis, apical 4- and 2-chamber views at a Nyquist limit of 50 to 60 cm/s (2). In addition, proximal flow convergence was recorded using a magnified 4-chamber view, with baseline shift of the Nyquist limit to optimize visualization of flow convergence (2) (Figs. 2A and 2B). All echocardiogram clips (moving images) were available on the Website. There were no still frame images. The reader, however, was able to play the images, stop frame them, magnify them, perform frame-by-frame analysis, as well as take measurements using calibration markings and caliper. All imaging were performed with the iE33 ultrasound system (Phillips Medical Systems, Andover, Massachusetts).

View larger version (61K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Limitation of PISA Radius for Assessment of MR Severity (A) Clear definition of the aliasing line of the proximal isovelocity surface area (PISA) is critical for accurate assessment of mitral regurgitation (MR) severity. As shown in this apical 4-chamber view, the aliasing line of the isovelocity surface and the regurgitant orifice are well visualized, therefore reducing the potential overall interobserver variability in the assessment of MR severity. (B) In this apical 4-chamber view, the MR isovelocity surface is readily identifiable; however, precise location of the regurgitant orifice is difficult to judge. This makes the assessment of proximal isovelocity surface area radius less reliable and increases the interobserver variability in the assessment of MR severity.

View larger version (64K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Limitation of VC Width for Assessment of MR Severity (A) As shown in this parasternal long axis view, the transition from proximal flow conversion (arrow) to the vena contracta (VC) of mitral regurgitant (MR) jet is visualized facilitating identification of the effective regurgitant orifice. A clearly defined VC neck is essential for reliable assessment of MR severity. (B) In this parasternal long axis view, the transition from the proximal flow conversion to the VC is not well visualized. Consequently, the identification of the effective MR orifice is challenging. No clear VC neck is seen; therefore, this introduces more potential interobserver variability in the assessment of MR severity.

where R_PISA is PISA radius (cm), V_aliasing is aliasing velocity of the proximal flow convergence (cm/s), and V_max is maximal velocity of continuous wave Doppler MR signal (cm/s).

Definitions.   The MR was graded as severe or nonsevere for each echocardiogram-Doppler parameter. MR was considered severe if VC was 7 mm, if EROA was 40 mm², or the jet size–based grade was 3 or 4; MR was considered nonsevere if VC was 6.9 mm, EROA was 39 mm², or jet size–based assessment graded it as 1 or 2.

The MR jet was considered eccentric if it was in close contact with the mitral leaflet behind the regurgitant orifice, and impinged to the medial or lateral wall of the left atrium, whereas central jets were initially directed into the center of the left atrium (2,3).

For each patient, temporal variability of PISA radius and VC width were assessed by measuring these parameters frame by frame throughout systole. We classified PISA and VC as having substantial pansystolic variation if there was greater than a 30% difference between the greatest and smallest values of any 2 different frames of the same cardiac cycle.

We classified PISA as nonspherical if the maximal and minimal radius of the proximal flow convergence demonstrated a greater than 30% variation within 1 cardiac cycle.

We used a cutoff of 30% to define substantial temporal variability of PISA radius and VC width as well as PISA sphericity to account for a 7% to 8% intraobserver variability of the small-scale measurements in our laboratory. In addition, a 30% difference in these parameters was readily detectable by visual assessment.

Figure 3 demonstrates identification of the effective regurgitant orifice, which was defined as visible if the transition of proximal flow convergence to the VC was clearly identifiable.

Overall, raw interobserver agreement (percent agreement) of 80% was classified as substantial agreement as this agreement rate was considered clinically adequate by all investigators. Values between 60% and 79% were classified as fair agreement and values below 60% as poor agreement (notably least possible interobserver agreement is 50%, which practically is equivalent to maximal disagreement).

Statistical analysis.   Statistical analysis was performed with the SPSS 13.0 software (SPSS Inc., Chicago, Illinois). Continuous data are presented as mean ± SD. Categorical data are presented as absolute number or percentages. The significance level was set at p = 0.05.

Interobserver agreement was assessed using the overall raw agreement (percent agreement) and the Fleiss kappa statistic (12). Fleiss multirater kappa coefficient is an agreement rate adjusted for chance rate of agreement, and it was calculated using the Online Kappa Calculator developed by Randolph (13). For this purpose, we used Randolph's multirater variation of Brennan and Prediger's (14) free-marginal kappa. Raw agreement and multirater kappa were calculated for 3 methods (VC, PISA, and jet area–based MR severity) in 16 patients by 18 observers and were calculated for each of the individual patients to determine the range of agreement within each method across all participants. Subsequently, cumulative raw agreement and multirate kappa were calculated for 3 study methods in patients with substantial raw agreement (80%) and those with suboptimal raw agreement (<80%).

Mean and 95% confidence intervals of multirater kappa were derived for 3 study methods and t test was used for comparison of multirater kappa among various study methods.

The MR characteristics thought to be clinically significant were dichotomized. Fisher exact test was used to compare the significance of these predictive parameters on raw agreement of 80% versus <80%. Significant variables were included in the multivariate logistic regression analysis to predict raw agreement 80%.

A p value <0.05 was considered significant for all analyses.

	Results

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Baseline characteristics.   Clinical and echocardiographic characteristics of 16 patients studied are summarized in Table 1: mean age was 69 ± 12 years and 56% were men. Eight (50%) had functional MR (6 with ischemic and 2 with dilated cardiomyopathy); 8 cases were degenerative (5 with mitral valve prolapse and 3 with flail leaflet). In 6 patients with functional MR, the jet was central. In all 8 degenerative MR patients and 2 functional MR cases, the jet was eccentric. For both the PISA radius as well as for VC width 7 (5 degenerative and 2 functional MR) cases demonstrated 30% frame-by-frame variability, whereas in the rest of the cases, the variability in these parameters was not substantial. The effective regurgitant orifice in the parasternal long axis view was visualized in 7 other cases (Fig. 2A).

Table 2 shows the proportion of observers who rated MR as severe according to various assessment methods in each patient. Using the parameter of jet area, echocardiologists graded MR as severe in 169 of 273 (62%) instances: using VC, MR was graded as severe in 74 of 206 (36%); and using PISA, measurements were consistent with severe MR in 85 of 207 (41%) times (p < 0.001).

Figure 4 shows the absolute and percentage distribution of substantial (raw agreement 80%), fair (raw agreement 60% to 79%), and poor (raw agreement <60%) agreement for 3 study parameters. Raw agreement 80% was observed only in 7 (44%) patients for jet area–based assessment. In this subgroup, cumulative kappa coefficient was 0.72 (95% CI: 0.68 to 0.76). Substantial agreement for VC was achieved also in 7 (44%) cases, whereas kappa in this subgroup was 0.61 (95% CI: 0.58 to 0.64). For PISA measurement, substantial agreement was present in 6 (38%) patients, kappa 0.85 (95% CI: 0.84 to 0.86). The difference was not significant among the 3 study parameters. In the rest of the cases, the agreement was fair or poor.

View larger version (29K): [in this window] [in a new window] [Download PPT slide]   Figure 4 Distribution of Overall Raw Interobserver Agreement for Assessment of MR Severity Substantial (raw agreement 80%), fair (raw agreement 60% to 79%), and poor (raw agreement <60%) interobserver agreements are shown for 3 study parameters for 18 observers. Out of 16 patients, substantial agreement was achieved in 44% of cases for mitral regurgitation (MR) jet area, 44% of patients for vena contracta method, and only 38% for effective regurgitant orifice area (EROA) based on proximal isovelocity surface area radius.

View larger version (24K): [in this window] [in a new window] [Download PPT slide]   Figure 5 Distribution of Substantial Interobserver Agreement Among Echocardiologists Practicing in a Single Center and Multiple Centers Eighteen cardiologists practicing at 11 different institutions in the U.S., Japan, and Israel assessed mitral regurgitation (MR) severity using 3 methods in 16 patients. In addition, interobserver agreement for assessment of MR severity was compared among the 6 echocardiologists practicing within a single institution to the agreement of the echocardiologists from multiple institutions. There was a similar, suboptimal rate of substantial interobserver agreement (raw agreement 80%) for all 3 color flow Doppler parameters among interpreters from both single center and multicenter interpreters.

In univariate analysis, the statistically significant predictors for raw agreement 80% for VC were central MR (p = 0.013) as well as an identifiable effective regurgitant orifice (p = 0.049). Whereas in the multivariate analysis, only the measure of an identifiable effective regurgitant orifice showed a significant predictive power of raw agreement 80% (p = 0.035) (Table 3).

For the PISA radius measurement, the presence of a central MR jet (p = 0.003), fixed proximal flow convergence (p = 0.025), and functional etiology (p = 0.049) were statistically significant univariate variables for prediction of raw agreement 80%. By multivariate analysis, central regurgitant jet morphology was the only significant predictor of raw interobserver agreement 80% (p = 0.02) (Table 3).

	Discussion

Top Abstract Methods Results Discussion Conclusions REFERENCES

 
This is the first multicenter study to evaluate the interobserver agreement of the quantitative parameters of VC width and PISA to differentiate severe from nonsevere MR. We found that classification of MR as severe as opposed to nonsevere using the quantitative CFD parameters of VC and PISA yielded only fair interobserver agreement (kappa: 0.28 to 0.37). The interobserver agreement for qualitative assessment for identifying severe from nonsevere MR was similar to the quantitative methods (kappa: 0.32). Our study group was composed of clinically experienced, practicing echocardiologists from 11 different academic institutions. Furthermore, we found that the interobserver agreement among echocardiologists practicing and instructing within the same institution was similar to the multicenter interobserver agreement and inferior to previously reported studies from single institutions validating the use of PISA and VC (3,6–11).

The VC width and EROA calculated by PISA are both affected by valve morphology and color flow jet characteristics. Incorporation of echocardiographic and etiologic variables in univariate and multivariate analysis revealed some of the sources of disagreement in our study. Various echocardiographic parameters were found to be significant in predicting good agreement for each study method in the univariate analysis. However, the presence of a central regurgitant jet was the only independent discriminator between suboptimal (raw agreement <80%) and substantial reproducibility (raw agreement 80%) for PISA radius measurement. In addition, the identification of an effective regurgitant orifice was the single multivariate predictor of raw agreement 80% for VC measurement.

Depending on whether observers use standardized measurements in an echocardiographic core laboratory, in a rigorously controlled research setting, or whether the MR grade is assessed by multiple enrolling sites with multiple echocardiologists, the rate of agreement is markedly different. Reliability of MR classification was reported in the EVEREST I (Endovascular Valve Edge-to-Edge Repair Study) trial. Two qualitative parameters—CFD jet characteristics and pulmonary vein flow—and 4 quantitative parameters—VC width, regurgitant volume, regurgitant fraction, and EROA—were evaluated. Parameters were integrated to form composite MR grade. Individual parameters and composite MR severity were found to be reproducible (15). However, considerable disagreement was reported in MR severity grading among echocardiogram readers in the Acorn Clinical Trial (16). All studies were interpreted to show significant MR at enrolling sites, but the core laboratory found that 41% of patients did not have significant MR: 7.4 % of patients had no detectable MR, 10.6% had mild MR, and 23.3% had moderate MR. Thomas et al. (17) proposed an MR index of 6 different indicators of MR: jet penetration into the left atrium, PISA radius, continuous wave jet intensity, pulmonary artery pressure, pulmonary venous flow pattern, and left atrial size. However, there was still a considerable overlap between moderate and severe MR (17).

There are several potential explanations for the limited reproducibility for the assessment of MR severity. Qualitative assessment of mitral regurgitation based on jet area varies on any given still frame and may thus be mischaracterized due to the frame-by-frame change in jet size. Whereas the eye rapidly integrates the change in jet area over time, this type of visual estimation can be highly subjective and varies among observers' assessment. The etiology of MR, the mitral valve morphology, and the regurgitant jet characteristics can further compound the MR assessment (4,5). Sources of error in the measurement of PISA include the presence of an eccentric jet, nonhemispheric geometry of proximal flow convergence, imprecise identification of regurgitant orifice (Fig. 2), and dynamic changes of PISA radius throughout systole (6,7). As with PISA, inherent characteristics of MR can influence the ability to accurately determine the VC width. The limitations of VC include an eccentric MR jet, dynamic VC, and inadequate visualization of any of the 3 components of VC (Fig. 3): proximal flow acceleration, the VC, and the downstream expansion of the jet (3,4).

The American Society of Echocardiography 2003 guidelines for the evaluation of valvular regurgitation emphasize an integrated approach for the classification of MR severity (2). However, in a subsequent large retrospective study in which severity of MR was quantified by Doppler echocardiography, 198 patients with an EROA greater than 0.40 cm² had a 4% per year risk of cardiac death during a mean follow-up period of 2.7 years (18). These findings largely contributed to the recent American College of Cardiology/American Heart Association 2008 guideline (1) recommendation to consider mitral valve surgery for asymptomatic patients with severe MR. Given the current recommendations for surgery on asymptomatic patients with severe MR, it is crucial to accurately differentiate severe from nonsevere MR. However, our study demonstrates that not only qualitative CFD but also quantitative CFD parameters have limited reproducibility and thus may be suboptimal in the clinical setting. We believe that the findings of our study, which identifies the potential difficulties in reliability to differentiate severe from nonsevere MR, support the concept of Gaasch and Meyer (19), namely "to question the diagnosis of severe chronic MR when little or no left ventricular or left atrial enlargement is found."

Study limitations.   The relatively small number of patients studied (n = 16) is a limitation. However, there were 18 observers and consequently each study parameter was assessed over 200 times. Small sample size may result in overfitted models. However, it will be practically difficult to have 18 cardiologists evaluate MR in a bigger sample size by 3 different methods, although we do realize that it would be ideal to have a bigger sample size. We were attempting to differentiate severe from nonsevere MR, and we have not assessed entire spectrum of MR severity. Had patients with mild MR been included in this study, the interobserver agreement may have been better. The absence of a true gold standard for MR assessment is a potential limitation for any study as it precludes the evaluation of the accuracy of the interpretations. In the absence of such a gold standard, substantial variation exists in the classification of MR as severe in the same patient depending on the method used. These differences limit raw agreement rate maximums to an extent that readers may not appreciate.

Clinical implications.   As color Doppler flow methods have limited interobserver agreement, the classification of MR as severe and clinical decision making in patients with MR should incorporate the use of additional less equivocal and more reproducible parameters such as mitral inflow pattern, MR jet continuous Doppler profile, mitral inflow pattern, pulmonary venous flow, and mitral valve morphology, as well as left ventricular and left atrial dimensions and left ventricular systolic function and pulmonary artery systolic pressure as recommended by the American Society of Echocardiography (2).

	Conclusions

Top Abstract Methods Results Discussion Conclusions REFERENCES

 
The presence of a central MR jet improves the reproducibility of EROA assessment by PISA and the ability to identify the effective regurgitant orifice significantly enhances interobserver agreement of VC assessment. The VC, PISA, and CFD regurgitant jet–based assessments of MR grade have substantial interobserver agreement. Use of the VC and PISA method in routine clinical practice, and for clinical decision making based solely on EROA calculation in asymptomatic MR patients may be problematic.

^_* Reprint requests and correspondence: Dr. Robert J. Siegel, 8700 Beverly Boulevard, Room 5623, Los Angeles, California 90048-1804 (Email: siegel{at}cshs.org).

Manuscript received May 14, 2009; revised manuscript received September 22, 2009, accepted September 28, 2009.

	REFERENCES

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This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Biner, S. Articles by Siegel, R. J. Search for Related Content PubMed Articles by Biner, S. Articles by Siegel, R. J. Related Collections Related Article