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Three-Dimensional Versus Two-Dimensional Echocardiographic Assessment of Functional Mitral Regurgitation Proximal Isovelocity Surface Area

Ashikhmina, Elena MD, PhD; Shook, Douglas MD; Cobey, Fred MD; Bollen, Bruce MD; Fox, John MD; Liu, Xiaoxia MS; Worthington, Andrea BA; Song, Pingping MD; Shernan, Stanton MD, FAHA, FASE

doi: 10.1213/ANE.0000000000000409
Cardiovascular Anesthesiology: Research Report
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BACKGROUND: The geometric shape of the mitral regurgitation (MR) proximal isovelocity surface area (PISA) is conventionally assumed to be a hemisphere (HS). However, in functional MR, PISA is frequently neither an HS nor a hemiellipse (HE) but is often asymmetric and crescent shaped. We used 3-dimensional transesophageal echocardiographic (3D TEE), full-volume data sets to directly measure the PISA and subsequently compared calculated values of effective regurgitant orifice area (EROA) with conventional 2D TEE techniques. EROA calculations from all PISA measurements were finally compared with the cross-sectional area at the vena contracta, a well-validated reference measure of the functional MR orifice area.

METHODS: Twenty-four cardiac surgical patients with functional MR, who underwent routine intraoperative TEE examinations with a 3D matrix array probe (X7-2t; IE33; Philips Healthcare, Inc., Andover, MA) were retrospectively evaluated for MR severity using quantitative 2D and 3D TEE-derived techniques. Conventional 2D TEE methods were used to estimate PISA assuming an HS shape and an HE shape. In addition, direct measurement of the 3D PISA was obtained (QLab, Philips Healthcare, Inc.) from corresponding full-volume, color-flow Doppler data sets. EROAs calculated from HS- and HE-PISA techniques were compared with the same values obtained from 3D TEE PISAs. EROAs obtained from all 3 PISA techniques were subsequently compared with vena contracta area.

RESULTS: Three-dimensional PISA was significantly larger than both HS-PISA and HE-PISA (mean ± SD: 4.65 ± 2.03 cm2 vs 2.10 ± 1.58 cm2 and 2.75 ± 1.42 cm2; both P < 0.0001), respectively. HE-PISA was also larger than HS-PISA (P = 0.042). In addition, 3D EROA was larger than both HS- and HE-acquired EROAs (mean ± SD: 0.44 ± 0.21 vs 0.19 ± 0.12 cm2 and 0.26 ± 0.14; both P < 0.0001), respectively, while HE-EROA was larger than HS-EROA (P = 0.024). Vena contracta area correlated well with 3D EROA (Spearman r = 0.865), HS-EROA (Spearman r = 0.820; P < 0.001) and HE-EROA (Spearman r = 0.819). However, the difference between vena contracta area and 3D EROA was significantly less than the differences between vena contracta area and either 2D HS- or 2D HE-EROA (P < 0.0001).

CONCLUSIONS: Quantitative assessment of functional MR severity by 3D TEE may be superior to 2D methods by permitting more direct measures of PISA. Two-dimensional TEE techniques for assessing functional MR severity that rely on an HS- or HE-PISA shape may underestimate the EROA due to geometric assumptions that do not account for asymmetry.

Published ahead of print August 27, 2014.

From the *Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; Department of Anesthesiology, Tufts University School of Medicine, Boston, Massachusetts; and International Heart Institute of Montana, Missoula, Montana.

Published ahead of print August 27, 2014.

Accepted for publication June 2, 2014.

Funding: Departmental funding, Brigham and Women’s Hospital, Boston, MA. The source of funding had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work did not receive any extramural funding.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Stanton K. Shernan, MD, FAHA, FASE, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115. Address e-mail to sshernan@partners.org.

The assessment of mitral regurgitation (MR) severity remains a cornerstone in the echocardiographic evaluation of patients with mitral valve (MV) disease. Qualitative and semiquantitative echocardiographic measures including color-flow Doppler (CFD) jet area are commonly used because of their practical value and ease of technical acquisition.1–3 However, these relatively simple measures are easily influenced by loading conditions and receiving chamber pressure.4 Consequently, currently published guidelines recommend the use of an integrated approach for the echocardiographic evaluation of MR, including both qualitative and quantitative measures.1,2

The proximal isovelocity surface area (PISA) or flow convergence technique for assessing MR severity uses a quantitative method to calculate the maximum instantaneous, effective regurgitant orifice area (EROA) based on the hydrodynamic principle that states that, as blood approaches an incompetent valve orifice, its velocity increases in the left ventricle (LV) to form concentric, approximately hemispheric (HS) shells of decreasing surface area that can be visualized with CFD.1,5 The HS surface area of the PISA is typically calculated from its measured radius (r), according to the formula: PISA = 2πr2. The PISA can then be multiplied by the MR aliasing velocity to obtain the regurgitant flow, which begins on the LV side of the incompetent MV orifice. The regurgitant flow that proceeds through the MV is the product of the peak velocity of the MR jet and the EROA. Since regurgitant flow on each side of the MV must be equal, the EROA can be calculated by dividing the flow on the LV side of the MV (PISA × MR aliasing velocity) by the peak velocity of the MR jet through the valve.1,2

Despite recommendations to incorporate PISA into the echocardiographic evaluation of MR severity, this technique has been associated with several limitations including decreases in accuracy for eccentric compared with central MR jets,1 inaccuracies in measuring the PISA-r,6,7 and significant interobserver variability.8 The assumption that PISA is an HS can be particularly problematic in patients with functional MR, which is a subcategory of MR mechanisms associated with structurally normal, yet apical tethered MV leaflets due to LV remodeling and dysfunction. Compared with patients with degenerative disease, the PISA in patients with functional MR is more likely to be hemielliptical (HE) or crescent shaped rather than the conventional HS.9–11 Inaccurately relying on the assumption that a PISA is an HS may result in significant underestimation of the calculated EROA and MR severity.9,10 In a study of 303 ambulatory patients with ischemic MR, the incidence of cardiac death at 5 years with an EROA <0.20 mm2 vs ≥0.20 mm2 was significantly higher (43% ± 9% vs 63% ± 10%), respectively (P < 0.001).12 Thus, accurate determination of the EROA has important clinical implications.

We hypothesized that conventional 2-dimensional (2D) echocardiographic techniques that assume an HS- or HE-PISA shape may not enable accurate measurements of EROA in patients with functional MR. To test this hypothesis, we first used 3D transesophageal echocardiography (TEE) to directly measure functional MR PISA, thereby avoiding any geometric assumptions and, second, compared corresponding calculated EROAs with those acquired using conventional HS and HE calculations of PISA. Finally, we compared each of the 3 EROAs to the cross-sectional area of the vena contracta (VCA), which is a well-validated reference measure of the functional MR orifice area.1,2 The VCA is conventionally obtained using 3D echocardiography technology that enables the acquisition of an accurate plane parallel to the minimal area of the jet surface area immediately distal to the regurgitant orifice.1

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METHODS

Study Population

The data were collected as part of an IRB-approved protocol with a waiver of informed consent. Twenty-four consecutive cardiac surgical patients (11 men; 13 women; 65 ± 17 years old), with at least mild functional MR quantified by preoperative CFD jet assessment,1 were enrolled at the Brigham and Women’s Hospital from 2010 to 2013. Functional MR was defined as MR resulting from apical tethering and malcoaptation of otherwise structurally normal MV leaflets.13 All enrolled patients had primarily bileaflet tethering and an associated single jet of central functional MR. We excluded technically inadequate studies and patients with structural abnormalities of the mitral leaflets, multiple significant MR jets, or those in atrial fibrillation.

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Intraoperative 3D TEE Data

Intraoperative 3D TEE images were obtained retrospectively from a database, consisting of routinely performed 2D and 3D TEE examinations. All intraoperative TEE images were acquired before the initiation of cardiopulmonary bypass, by National Board of Echocardiography–certified echocardiographers, using matrix array probes (X7-2t; IE33; Philips Healthcare, Inc., Andover, MA) capable of acquiring fully sampled 3D images. All measurements were acquired from 3D TEE full-volume data sets, which included both gray scale images of the MV apparatus and superimposed simultaneously acquired CFD images of the MR jet set initially at a Nyquist limit of 50 to 60 cm/s.1 Volume rates in the range of 30 to 40 Hz were enabled to assure optimal temporal resolution, first by adjusting the pyramid-shaped region of interest to the smallest volume that encompassed the entire mitral complex and second by using a routine protocol for obtaining hybrid reconstruction full-volume CFD data sets from 14 sequential heartbeat subvolumes, which were gated to the electrocardiogram while mechanical respiration was temporarily suspended to prevent stitching artifacts.

Measurements of HS-, HE-, and 3D PISA as well as VCA were all obtained off-line (Qlab, Philips Healthcare, Inc.) by perioperative echocardiographers with significant experience working with this software program. These measurements were acquired at the midsystolic frame, after standardizing the gray scale and color scales set to manufacturer’s default setting at 50%.14 The images were presented in 4 quadrants each derived from the 3D data set, including three 2D orthogonal anatomic planes (2 long-axis views: midesophageal 5-chamber equivalent and midesophageal mitral midcommissural equivalent view) and 1 short-axis view parallel to the annulus at the base of the PISA. The fourth quadrant represented a 3D volume-rendered view (Fig. 1).

Figure 1

Figure 1

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HS-PISA Measurement

Conventional 2D HS-PISAs were obtained from the displayed midesophageal 5-chamber equivalent view by measuring the r of the first aliasing velocity with the Nyquist limit adjusted off-line to 30 to 40 cm/s and using the formula: PISA = 2πr21,15 (Fig. 1).

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HE-PISA Measurement

HE-PISAs were obtained by measuring its r from the first aliasing velocity and diameter (d1: PISA width) in a midesophageal 5-chamber equivalent view identical to the technique for the HS-PISA and its diameter (d2: PISA length) in the corresponding orthogonal, midesophageal mitral midcommissural view15 (Fig. 1). The HE-PISA was then calculated as previously described from these 3 orthogonal parameters according to Thomsen’s formula10,11,16–18:

where P = 1.6075.

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Three-Dimensional PISA

Three-dimensional PISAs were calculated as follows using a novel off-label adaptation of commercially available software (Qlab; MVQ; Philips Healthcare, Inc.).

  1. Initially, 4 primary perimeter reference points or fiducials at the anterior, posterior, anterolateral, and posteromedial borders of the PISA were manually tagged on the corresponding 2 long-axis orthogonal planes.
  2. The remainder of the PISA perimeter was then manually outlined by delineating intermediate reference points in 18 radial planes (i.e., 36 reference points), which were circumferentially advanced around the long axis (Fig. 2).
  3. The contoured dome of the PISA was then manually traced (6 trace points per centimeter) without geometric assumptions, along parallel and equidistant 2D long-axis planes from its lateral to medial border.
  4. The total 3D PISA was calculated from the length of each parallel contoured surface, using numerical integration of the area between manually traced planes (Fig. 2). The reconstructed surface area was subsequently displayed as a color-coded, 3D-rendered surface representing a topographical map of the PISA (Fig. 2).
Figure 2

Figure 2

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Effective Regurgitant Orifice Area

The MR peak velocity for each patient was measured from the routinely collected, continuous-wave Doppler flow velocity profiles of the MR jet acquired immediately after the 3D full-volume data set used for measuring PISA and VCA. MV EROA for the HS-, HE-, and 3D PISA measurements for each patient was calculated from the formula: EROA = PISA × aliasing velocity/MR peak velocity.1,15

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Vena Contracta Area

VCA was measured in the same midsystolic frame of the same 3D TEE CFD, full-volume data set as the PISA measurements. Specifically, the Nyquist limit was kept at the original levels between 50 and 60 cm/s to avoid over- or underestimation of VCA.2,14 The 3D data set was then cropped to develop a short-axis view perpendicular to the MR jet direction, until the smallest jet cross-sectional area was visualized at the level of the vena contracta, just distal to the regurgitant orifice as previously described1,14,15 (Fig. 3). VCA was then measured, blinded to all other data, by manual planimetry of the CFD signal (Fig. 3).

Figure 3

Figure 3

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Statistics

We calculated that 90% power would be achieved with a sample of 20 patients to detect an effect size of 0.3 cm2 with a type I error of 0.05 using a 2-sided paired t test of the difference between means. We are not aware of any other published studies specifically addressing our technique for direct 3D measurement of PISA without any geometric assumptions. Thus, this derived effect size was based on currently available related, yet limited, literature9–11,18 and current guideline recommendations regarding the specific value that best represents a significant difference between clinically relevant grades of MR severity.1,2a Basic descriptive statistics were calculated to present the data as mean ± SD for continuous variables. Nonparametric Wilcoxon signed-rank tests were used to assess the differences among variables. A Bonferroni correction was used to account for multiple tests that were performed on the same data set. Specifically, we multiplied the unadjusted P values by the number of hypotheses tested (Table 1: pairwise differences). A P value of <0.05 was considered to be statistically significant. Spearman ρ correlation coefficients and 95% confidence interval (CI) were calculated by using Fisher z transformation (SAS Proc Corr [Spearman Fisher], SAS Institute, Cary, NC) to test the correlations between VCA and HS-EROA, HE-EROA, and 3D EROA. Agreement between VCA HS-EROA, HE-EROA, and 3D EROA was determined by Bland-Altman analysis. A second independent observer repeated all measurements to assess interobserver variability. Intraclass correlation coefficients were calculated for each of the response variables to evaluate the consistency or reliability of measurements made independently. The analyses were performed with SAS version 9.3 (SAS Institute).

Table 1

Table 1

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RESULTS

Three-dimensional PISA was significantly larger than both HS-PISA and HE-PISA (mean ± SD: 4.65 ± 2.03 vs 2.10 ± 1.58 cm2 and 2.75 ± 1.42; both P < 0.0001), respectively (Table 1). HE-PISA was also larger than HS-PISA (P = 0.042). In addition, 3D EROA was larger than both HS- and HE-EROA (mean ± SD: 0.44 ± 0.21 vs 0.19 ± 0.13 cm2 and 0.26 ± 0.14; both P < 0.0001), respectively. Furthermore, HE-EROA was larger than HS-EROA (P = 0.024). While the differences between VCA and 2D HS-, 2D HE-EROA, and 3D EROA were statistically significant (P < 0.001, P < 0.001, P = 0.004, respectively), VCA correlated well with 3D EROA (Spearman r = 0.865; 95% CI, 0.70–0.94), HS-EROA (Spearman r = 0.820; 95% CI, 0.61–0.92), and HE-EROA (Spearman r = 0.819; 95% CI, 0.61–0.92; Fig. 4). However, the absolute differences between VCA and 3D EROA were significantly less than the absolute differences between VCA and either 2D HS- or 2D HE-EROA (in each case P < 0.0001; pairwise Wilcoxon signed-ranks test; Bonferroni corrected; Fig. 4). This can be seen in the limits of agreement plots (Fig. 4) that demonstrate that the agreement between VCA and 3D EROA (bias: 0.151; limits of agreement: −0.201 to 0.504; SD: 0.18) was superior to 2D HS (bias: 0.401; limits of agreement: P = 0.073 to 0.875; SD: 0.24) or 2D HE-EROA (bias: 0.332; limits of agreement: P = 0.067 to 0.731; SD: 0.20). All measured variables achieved excellent interobserver reliability (intraclass correlation coefficient >0.9; all lower bounds of the 95% CI were >0.8).

Figure 4

Figure 4

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DISCUSSION

The use of PISA as a quantitative measure of MR severity has been well described over the past 2 decades.5 Currently, PISA and associated derived calculations including EROA are recommended by the American Society of Echocardiography as part of an integrated echocardiographic assessment of MV dysfunction.1 Despite the respect for the use of PISA, several limitations for this technique have been identified, especially in patients with functional MR where assumptions about its HS shape acquired with 2D echocardiography may limit its universal usefulness. We now show that when functional MR PISA is directly measured without geometric assumptions using 3D TEE, corresponding calculated EROAs are almost 70% larger compared with similar measurements acquired from conventional HE-PISAs and more than twice as large as EROAs calculated from HS-PISAs (Table 1). Furthermore, the differences between measurements of VCA and 3D EROA are significantly less than the difference between VCA and either 2D HS- or 2D HE-EROA. Thus, in patients with functional MR, EROAs calculated from either an HS- or HE-PISA may not accurately reflect MR severity.

In patients with functional MR, the general shape of the leaflet malcoaptation orifice has been described as asymmetric and assuming an elliptical or even crescent shape, rather than the more conventional circular shape often observed in patients with degenerative MV disease.9,17,18 For example, Matsumura et al.9 used 3D transthoracic echocardiography (TTE) to compare PISA in 27 patients each with functional MR versus those with degenerative disease presenting with MV leaflet prolapse and demonstrated that the PISA in patients with functional MR was comparatively elongated and curved along the commissural plane, whereas patients with degenerative disease had more symmetric, round-shaped PISAs. Using an HS-PISA method would have underestimated the EROA by 24% in those patients with functional MR.9 Yosefy et al.10 used 3D TTE to characterize PISA in 50 patients as either HS or HE shaped. The 2D EROAs were computed from the conventional HS assumption in their study, while 3D echocardiography data sets were used to calculate MR EROA by applying an HE formula. Compared with quantitative Doppler EROAs (i.e., Mitral Inflow [mL] − Aortic Outflow [mL]/MR Time-Velocity Integral [cm]) as an independent comparison, the 2D echocardiography HS technique significantly underestimated EROA (0.34 vs 0.48 cm2), while the HE-EROA was not significantly different (0.52 vs 0.48 cm2). Forty-five percent of patients with at least moderate MR by Doppler EROA (i.e., >0.3 cm2) were underestimated as having less than moderate MR by 2D EROA.10 Finally, in a separate study, Matsumura et al.18 studied 30 patients with functional MR and compared EROAs calculated from PISA using the standard 2D HS method with those acquired from 3D TTE echocardiography using an HE formula. Compared with EROA calculated from a 2D quantitative Doppler method, the HE-PISA technique underestimated EROA by only 26%, whereas the underestimation by the HS-PISA method was 49%. Thus, these studies demonstrate that the calculation of PISA as an HS may not be valid in patients with functional MR in whom an HE shape may be more appropriate.

We have now shown that even an HE shape as defined mathematically in all of the aforementioned studies may not be consistently valid, since it still assumes certain geometric uniformity.11 In our study, we used 3D TEE, high volume rate data sets to directly measure PISA independent of its shape and geometric assumptions. Inspection alone of the 3D PISA in patients with functional MR demonstrates that similar to VCA, it has an asymmetric, crescent- or sickle-shaped base due to additional extensions at the anterolateral and posteromedial borders and is therefore larger than the corresponding, symmetric circle (HS base) or oval (HE base) that could accommodate its perimeter (Fig. 5). This observation alone strongly supports our results demonstrating that, in patients with functional MR, conventional 2D HS and HE techniques for obtaining PISA may significantly underestimate corresponding EROAs.

Figure 5

Figure 5

We chose VCA as a comparative measure and reference method for EROA and MR severity. The VCA is the short-axis area of the MR jet and is conventionally obtained using 3D echocardiography technology, which enables the acquisition of an accurate plane parallel to the minimal area of the jet surface area immediately distal to the regurgitant orifice.1,14,19 Since the VCA is characterized by high-velocity flow acquired using CFD, it is smaller than the anatomic regurgitant orifice and is therefore more representative of a functional EROA. Similar to PISA, VCA and EROA are more representative of a static regurgitation orifice area, rather than a dynamic, anatomic orifice.17,20,21 We chose to use VCA as a comparative measure of EROA and MR severity for several reasons. First, VCA has already been frequently validated against nonechocardiographic techniques including ventriculography22 and magnetic resonance imaging (MRI)23 in the assessment of MR severity. While MRI might be considered the ultimate “gold standard” for assessing MR EROA, VCA has the advantage of being another echocardiographic technique that can permit measurements at approximately the same time as the PISA acquisition, thus avoiding inaccurate comparisons due to differences in hemodynamics that could influence measurements by an MRI examination that would need to be obtained at a different time. Second, VCA like 3D PISA manifests as an asymmetric, crescent shape in functional MR compared with organic MR24 and has already been used extensively as a comparative technique for evaluating PISA.12,25 However, while both are considered functional correlates of EROA, the techniques for acquiring each surrogate measure of MR severity differ, and therefore variation between the 2 measurements should be expected. Interestingly, similar to our study, VCA has been shown to be up to 30% larger than EROA acquired by HE-PISA in patients with functional MR.12 Differences between VCA measures of MR severity and other echocardiographic and nonechocardiographic techniques may be related to its susceptibility to pixilation and variability in acquisition and measuring techniques.14 We addressed the latter issue by standardizing our technique during VCA measurement to maintain the Nyquist limit between 50 and 60 cm/s and both color and gray scale gain at the 50% levels.2,14 In summary, our decision to use VCA was based on its practical value, noteworthy historical comparison with other nonechocardiographic techniques, and prior robust support in the literature for its use as a validation technique for evaluating PISA as a measure of MR EROA.

Certain limitations relevant to this study are worthy of further consideration. Our patient population included only those with a single primary jet of functional MR. While studies have identified 3D VCA as being a more accurate technique compared with 2D vena contracta width for measuring total EROA in patients with multiple jets,26 expectations for using multiple 2D or 3D PISAs may be impractical and unrealistic. In addition, while our patients had primarily symmetric bileaflet tethering with central jets, functional MR is dynamic, load dependent, and represents a spectrum of etiologies and mechanisms including those with asymmetric leaflet involvement, which may present with variations in EROA geometry.27,28 From a technical perspective, purported limitations of 3D CFD images have included concerns over the inability to obtain adequate temporal resolution to enable the accurate identification of specific events within the cardiac cycle. However, in our study, the use of routinely acquired full-volume, electrocardiogram-gated 3D data sets from 14 sequential heartbeat subvolumes while mechanical respiration was temporarily suspended permitted volume rates in the 30- to 40-Hz range without stitch artifact. This temporal resolution far exceeds values included in most investigations using this technology where reported data sets are often acquired from only 7 or fewer subvolumes, or even in real-time imaging where volume rates are frequently <20 Hz.24,25 Nonetheless, the described technique for acquiring 3D PISA requires significant time and experience to manipulate the images and use the software to consistently obtain accurate images. Finally, while others have reported challenges in even obtaining reproducible 2D PISA measurements,8 our respectable interobserver variability is most likely due to our investigators’ significant experience with the software used to perform the quantitative analyses.

A specific clinical outcome to address the relevance of using different PISA techniques or just VCA was also not addressed but certainly warrants further investigation. Due to the retrospective nature of our study, we were unable to determine the impact of this observation on clinical decision making. Nonetheless, according to values available in published guidelines, our data would correlate with a significant difference between a diagnoses of mild (HS-PISA EROA: 0.20 mm2) versus severe MR (3D PISA EROA: 0.46 mm2) for the same patient, only depending on the technique used to quantify MR severity.1 Furthermore, in patients with functional MR, thresholds of severity that are considered to have prognostic value include an EROA ≥20 mm.2,29 Thus, accurate determination of the EROA has important clinical implications. Finally, our data are consistent with the increasing popular opinion that based on discrepancies between conventional 2D quantitative measures of functional MR severity and VCA or even 3D PISA EROA, larger cutoff values may be warranted.24 Our intention, however, was not to demonstrate the practical clinical value of 3D PISA for determining EROA but rather to emphasize the importance of understanding the mechanism of functional MR and the potential for significantly underestimating MR severity if conventional 2D PISA techniques are used in this patient population. Recently described, semiautomated techniques for acquiring 3D PISA without geometric assumptions are currently available only for TTE data sets, but will most likely permit further valuable insight into the practical value of this measurement for assessing MR severity.30,31

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CONCLUSIONS

While the assessment of MR severity remains a cornerstone in the evaluation of patients with MV disease, it is important to consider limitations associated with qualitative and quantitative echocardiographic measures. The use of PISA is a well-recognized and recommended echocardiographic technique for assessing MR severity as part of an integrated approach.1 However, using 3D echocardiographic data sets acquired from patients with functional MR, we have now shown that PISA asymmetry may make conventional 2D echocardiographic techniques for calculating EROA obsolete. Further investigation is ultimately warranted to determine the clinical importance of considering the etiology of MV dysfunction when deciding on the optimal technique for its comprehensive evaluation.

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DISCLOSURES

Name: Elena Ashikhmina, MD, PhD.

Contribution: This author helped design the study, analyze the data, and prepare the manuscript.

Attestation: Elena Ashikhmina attests to having approved the final manuscript and the integrity of the original data and the analysis reported in the manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Douglas Shook, MD.

Contribution: This author helped analyze the data, collect the data, and prepare the manuscript.

Attestation: Douglas Shook attests to having approved the final manuscript.

Conflicts of Interest: Douglas Shook received honoraria for education in echocardiography from Philips Medical, Sorin Group, and Edward Lifesciences.

Name: Fred Cobey, MD.

Contribution: This author helped design the study, analyze the data, and prepare the manuscript.

Attestation: Fred Cobey attests to having approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Bruce Bollen, MD.

Contribution: This author helped design the study, analyze the data, and prepare the manuscript.

Attestation: Bruce Bollen attests to having approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: John Fox, MD.

Contribution: This author helped collect data, analyze the data, and prepare the manuscript.

Attestation: John Fox attests to having approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Xiaoxia Liu, MS.

Contribution: This author helped analyze the data and prepare the manuscript.

Attestation: Xiaoxia Liu attests to having approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Andrea Worthington, BA.

Contribution: This author helped collect the data and prepare the manuscript.

Attestation: Andrea Worthington attests to having approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Pingping Song, MD.

Contribution: This author helped collect the data and prepare the manuscript.

Attestation: Pingping Song attests to having approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Stanton Shernan, MD, FAHA, FASE.

Contribution: This author helped design the study, collect the data, analyze the data, and prepare the manuscript.

Attestation: Stanton Shernan attests to having approved the final manuscript and the integrity of the original data and the analysis reported in the manuscript and is the archival author.

Conflicts of Interest: Stanton Shernan serves as an educator for Philips Healthcare, Inc., and as an editor for E-echocardiography.com.

This manuscript was handled by: Martin J. London, MD.

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FOOTNOTE

a Reference #2, Table 3, indicates that an EROA difference of 0.05 cm2 is clinically significant. Reference #18, Table 1, shows that the SD for EROA with 2D echo is 0.1 cm2. The resulting effect size is 0.5 cm2. We powered our study for an effect size of 0.3 cm2, being conservative in design because of our use of nonparametric tests.
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