The echocardiographic evaluation of mitral regurgitation (MR) remains a cornerstone in the comprehensive review of patients with suspected valvular heart disease. MR mechanisms are commonly defined according to abnormalities of leaflet motion.1 Current American Society of Echocardiography guidelines pertaining to the use of echocardiography for the assessment of regurgitant valve lesions recommend an integrated approach using both qualitative and quantitative measures to evaluate MR severity.2 Diagnosing the etiology, mechanism, and severity of MR has important implications for correlating the extent of disease with symptoms and for determining the requirement for intervention, as well as the type and timing of medical treatment or surgery.3,4
The echocardiographic grading of MR severity involves many metrics, but typically focuses on the maximal extent of the MR jet, the regurgitant volume, and size of the effective regurgitant orifice area (EROA). However, the temporal pattern of MR throughout the systolic phase of the cardiac cycle usually is not emphasized as an area of primary focus. Topilsky et al.5 compared patients with degenerative mitral valve (MV) prolapse and mid-late systolic MR with those with holosystolic MR and noted that, despite identical jet areas and EROAs, the shorter duration of the mid-systolic MR yielded lower regurgitant volumes. Regurgitant volume rather than EROA was linked to outcome, including death from cardiac causes, admission for congestive heart failure, or new-onset atrial fibrillation. The authors concluded that clinicians should consider the timing of MR in clinical management.5
Differences in the temporal pattern of MR also have been reported between degenerative and functional MV disease. Patients with degenerative MV disease (DMVD) associated with excessive prolapse or flail segments often demonstrate a classic pattern with a single EROA peak, usually in mid-systole to late systole.6–9 Alternatively, patients with functional MR (FMR) characterized by systolic restricted leaflet motion exhibit a biphasic pattern with an initial EROA peak in early systole, followed by a decline in mid-systole and a final second peak in late systole.6–9 An appreciation of the characteristic dynamics of MR associated with different valve lesions is needed for an accurate assessment of MR severity.
The high temporal resolution afforded by M-mode has been used to delineate variations in the proximal isovelocity surface area (PISA) radius to extrapolate the temporal dynamics of the EROA.5–7 More recently, the vena contracta area (VCA) acquired from 3D echocardiographic full-volume color flow Doppler (CFD) data sets has become an established and validated technique for measuring the EROA.10–12 We hypothesize that the temporal pattern of VCA significantly differs between patients with FMR and DMVD.
Retrospective data were collected as a part of an IRB-approved protocol. Adult cardiac surgical patients who were admitted at the Brigham and Women’s Hospital between 2009 and 2012 with at least mild MR were identified. Patients were divided into 2 groups: those with FMR and DMVD. FMR was defined as MV incompetence resulting from apical tethering and malcoaptation of otherwise structurally normal leaflets.13 All included patients with FMR had primarily bileaflet tethering and an associated single jet of central MR. Patients with DMVD had a single, eccentric MR jet, with echocardiographic evidence of excessive leaflet motion presenting as leaflet prolapse or flail.14,15 Patients with technically inadequate studies, multiple significant MR jets, and those in atrial fibrillation were excluded.
Intraoperative 3D Transesophageal Echocardiography Data
Intraoperative 3D transesophaeal echocardiography (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 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.2 Volume rates in the range of 30 to 40 Hz were enabled to assure optimal temporal resolution, first by adjusting the pyramidal-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 VCA were obtained off-line (QLab, Philips Healthcare, Inc.) by echocardiographers. These measurements were acquired after standardizing the gray and color scales set to the manufacturer’s default setting of 50%.16,17 The VCA was measured with the Nyquist limit set to the original levels between 50 and 60 cm/s to avoid its over- or underestimation.17,18 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 described (Fig. 1).2,12,17,18 VCA was then measured by manual planimetry of the CFD signal in triplicate to obtain an average value. This same process was repeated for each systolic frame to create a series of sequential VCAs for each patient. An average of 12.2 ± 3.9 (range: 10–17) systolic frames was available per patient (Figs. 2 and 3).
To account for variation in the length of systole between the patients and the resultant variation in number of frames, the systolic time scale for each patient was normalized to a range of 0% to 100%. Subsequently, the series of VCAs for each patient was normalized by dividing each instantaneous area by the average VCA of the corresponding patient. Thus, each patient had an average VCA of 1.0 throughout systole, making the temporal pattern of regurgitation comparable between individual patients. The normalized VCAs for each patient were further analyzed by dividing each patient’s VCA series into terciles (i.e., 0%–33%, 34%–66%, and 67%–100% on the time scale) and averaging the normalized VCAs for each tercile. Each patient was therefore characterized by 3 average normalized VCAs corresponding to the 3 terciles of the time scale. The use of terciles was specifically chosen to best capture the temporal dynamics of MR and enable comparisons between the FMR and the DMVD groups.
We calculated that 86% power would be achieved with a sample of 20 patients per group to detect a difference in mean EROA between clinical groups of 0.4 cm2, assuming an SD for both groups of 0.4, using a 2-sided t test with α = 0.05. We are not aware of any other published studies specifically addressing our technique for comparisons of directly measured 3D VCAs. Thus, this derived effect size was based on currently available related, yet limited literature,6–12 and current guideline recommendations regarding the specific value that best represents a significant difference between clinically relevant grades of MR severity.2,18,a
Basic descriptive statistics were calculated to summarize the data as mean ± SD for continuous variables and proportions for categorical variables. Between-group comparisons of demographic and clinical variables were performed using t tests for continuous variables and χ2 tests for categorical variables.
The tercile averages were compared within and between the FMR and the DMVD groups using a mixed model that accounted for repeated subject measurements and included Satterthwaite degree of freedom adjustment for unequal variances. Pairwise tests within and between groups were Bonferroni-corrected for all 15 possible pairwise comparisons, with the 9 comparisons of interest reported here (6 within-group comparisons of the 3 terciles and 3 between-group comparisons of each tercile). Inter-rater reliability of the manually measured VCA tracings was assessed by having 2 clinicians independently perform the tracings on 20 randomly chosen patients (10 from each group), and the intraclass correlation coefficient (ICC) for agreement between the raters was calculated. ICCs were calculated using the SAS macro intracc.sas (documented here: http://support.sas.com/kb/25/031.html). All other analyses were performed using MATLAB® (MathWorks®, Natick, MA) or SAS v9.3 (SAS Institute, Cary, NC) using 2-tailed tests with α = 0.05.
Data were obtained from 42 cardiac surgical patients, including 22 patients (11 men) with a primary diagnosis of FMR and 20 patients (7 men) with DMVD. Patients with FMR were notably older (70.2 ± 12.4 vs 60.5 ± 14.1 years; P = 0.022) and had lower preoperative ejection fractions (37.5% ± 17.9% vs 59.5% ± 5.8%; P < 0.001; Table 1). Ninety-three percent of all patients underwent MV surgery, including 100% (n = 20) with DMVD and 86% (n = 19) with FMR (Table 1). Three FMR patients, including 1 heart transplant recipient, 1 patient receiving a left ventricular device, and 1 coronary artery bypass patient with only moderate MR, did not undergo an MV surgical procedure. Inter-rater reliability of VCA measurements was excellent, with an ICC for agreement between the 2 observers of 0.99 (95% confidence interval, 0.99–1.00).
Normalized VCAs obtained throughout systole in patients with FMR revealed a biphasic pattern with an initial early systolic peak (first tercile) followed initially by decreasing VCA in mid-systole (second tercile) and subsequently a second peak in late systole (third tercile; Figs. 2 and 4). Conversely, in patients with DMVD, normalized VCA consistently increased with a monophasic peak in mid- to late systole (Figs. 3 and 4).
Results of the mixed model showed statistically significant differences in normalized average VCAs across terciles throughout systole within each group (Fig. 5). Among the FMR patients, normalized average VCA in the early systolic (1.10 ± 0.32 cm2) and late systolic (1.11 ± 0.33 cm2) terciles were similar but were significantly greater compared with the mid-systolic tercile (0.79 ± 0.22 cm2; Bonferroni-corrected P = 0.0144 and P = 0.0106, respectively). Conversely, among the DMVD patients, the normalized average VCA in the mid-systolic tercile (1.37 ± 0.15 cm2) was significantly greater than late systolic (1.09 ± 0.18 cm2) and early systolic (0.53 ± 0.14 cm2) terciles (Bonferroni-corrected P < 0.0001 for both; Fig. 5). The normalized average VCA in the late systolic tercile was also significantly greater than the early systolic tercile in the DMVD group (P = 0.001). A comparison of the VCA terciles between groups revealed that the average VCAs were significantly higher in FMR patients during early systole (1.10 ± 0.32 cm2 vs 0.53 ± 0.14 cm2) but that DMVD patients had higher VCAs during the mid-systole (1.37 ± 0.15 cm2 vs 0.79 ± 0.22 cm2; P < 0.0001 for each comparison; Fig. 6). These differences are consistent with the patterns observed for each population (Figs. 2–4).
Conventional echocardiographic grading of MR usually focuses on quantifying its maximum severity. Dynamic changes in MR that develop throughout systole are usually not accounted for, even though there is often significant variation depending on the timing of the assessment and the mechanism. We have now shown that the VCA as a surrogate of EROA is dynamic and varies significantly throughout systole. Furthermore, the pattern of systolic variation in VCA is dependent on the mechanism of MR with significant differences evident in patients with DMVD compared with those with FMR. Patients with DMVD demonstrate an increasing, monophasic VCA, which peaks during mid- to late systole. Alternatively, patients with FMR have a characteristic biphasic pattern, where VCA peaks in very early and late systole and are significantly greater than the value of the mid-systolic VCA trough. Significant differences between FMR and DMVD patients were noted in VCA during early and mid-systole, thus supporting observations in previous studies that used conventional techniques involving EROA calculations by integrating changes in the PISA with continuous-wave Doppler-acquired MR velocities.6–8 Understanding the temporal patterns of MR may have important implications for correlating severity with clinical symptoms and LV remodeling, as well as for determining the optimal timing of interventions.3–5
Mitral Orifice Dynamics
Competent mitral leaflet coaptation requires a predominance of LV systolic closing forces relative to the apically directed tethering forces of the MV apparatus. MV leaflet coaptation is initially facilitated during isovolumetric contraction by closing forces, which develop while ventricular pressure increases. In patients with FMR and impaired contractility, the change in ventricular pressure over time (dp/dt) is diminished, thereby compromising optimal leaflet approximation and closure, while MV tethering forces predominate. This phenomenon, resulting in an initial peak in regurgitation in FMR patients, has been described as systolic “leaflet loitering.”7,19–21 A progressive increase in LV pressure relative to the tethering forces of the mitral apparatus favors further leaflet closure.22 When the aortic valve opens and the LV pressure peaks, maximal closing force is exerted on the MV, further improving the degree of coaptation, which results in a relative decrease in the EROA and MR.7,22,23 In mid- to late systole, the MV annulus expands radially, thereby decreasing leaflet coaptation.24,25 Furthermore, a gradual decline in LV pressure associated with ventricular emptying results in a decline in the transmitral pressure gradient while the tethering forces acting on the leaflets again predominate, resulting in a second regurgitant peak.7
The temporal pattern of regurgitation and EROA development in patients with DMVD is distinctly different from those with FMR. In DMVD, the closing forces predominate throughout systole, especially in the presence of normal contraction and excessively redundant MV leaflet tissue with either elongated or ruptured chords. Rather than facilitating leaflet coaptation, an increase in ventricular pressure actually significantly contributes to progressive leaflet billowing or discrete prolapse, thereby increasing EROA and regurgitation throughout systole.26 Finally, as the LV pressure declines after ejection in late systole, billowing forces subside and the EROA decreases before the onset of diastole.6
Thus, EROA can be dynamic and varies significantly throughout systole. Furthermore, we have now shown that the pattern of systolic variation in VCA as a measure of EROA depends on the mechanism of MR, with differences in patients with FMR compared with those with DMVD.
Temporal Dynamics in the Assessment of MR
Temporal differences in the mechanics of MV dysfunction have implications for the echocardiographic grading of MR severity. The American Society of Echocardiography guidelines include the VC width and EROA within a list of metrics for evaluating MR severity.2 Recently, VCA has received attention as a validated technique for assessing MR.10,12,17 As a surrogate of EROA, the VCA quantifies the hydraulic phenomenon of flow contraction, which changes in shape and size as leaflet coaptation evolves. However, a single static measurement is insufficient to represent this dynamic process.8,12 The biphasic pattern observed in FMR presents a particular challenge to the classic method of using the PISA to calculate the EROA, regurgitant volume, and regurgitant fraction. Classically, the calculation of EROA requires identification of the largest PISA and uses the peak transmitral pressure gradient and MR velocity.2 Paradoxically, in patients with FMR, the PISA has the smallest radius when the peak MR velocity is the greatest.6–8,27 In patients with DMVD, the largest EROA is more likely to occur during the maximal pressure gradient, temporally relating to the point of greatest regurgitation.6,8 Whereas the EROA calculated from PISA requires a single peak mid-systolic velocity, the VCA can be measured independently, thus facilitating a more comprehensive understanding of the dynamic nature of EROA.
When the temporal variation in EROA size and corresponding pressure gradients are considered, calculated regurgitant volumes approximate those measured with MRI more closely.6,8,27 Given these temporal differences, static metrics of EROA such as vena contracta width, VCA and PISA, may not be ideal indices of MR severity when different pathologic mechanisms are involved. Accordingly, the significant dynamic variation in VCA that we observed warrants further consideration when evaluating the severity of regurgitation in patients with either FMR or DMVD.
The dynamic nature of MR and its relation to underlying valvular pathology have been studied for decades and have historically been appreciated on physical examination during auscultation.28 However, the availability of high-fidelity 2D and more recent 3D echocardiography has enhanced our understanding of the pathologic mechanisms underlying these observations. Schwammenthal et al.6 evaluated patients with different MR etiologies by computing the instantaneous regurgitant flow rate from color M-mode recordings of the PISA and dividing them by the corresponding orifice velocity to first obtain the instantaneous orifice area and second to demonstrate differences among the biphasic, early, and late peaks in EROA among patients with FMR, compared with the monophasic mid- to late systolic EROA peak in patients with MV prolapse. Similar results were shown in a later study involving FMR patients, in which the time course of transmitral pressure and EROA (mitral regurgitant flow rate/peak MR velocity) was plotted to demonstrate that the mid-systolic decrease in EROA between the early and the late systolic peak mirrored the increase in transmitral pressure.7 These authors speculated that the EROA may vary in parallel with mitral annular area, which decreases to a minimum in mid-systole before increasing in late systole with atrial filling. In this investigation, the driving force of transmitral pressure on leaflet closure had a greater influence on EROA than changes in mitral annular area. This unique temporal pattern of MR flow and orifice area variation, which is dependent on the etiology of the regurgitant lesion, has also been validated by others using PISA and peak MR velocity to calculate EROA, as well as nonechocardiographic techniques, including electromagnetic flowmeters.8,9
Most earlier studies investigating the temporal patterns of MR required the acquisition of multiple echocardiographic-derived measures, including PISA techniques, to calculate EROA. Although current published guidelines recommend an integrated approach including qualitative and quantitative measures for the echocardiographic evaluation of MR,2,18 the use of the PISA technique requires the recognition of certain important challenges including (1) assumptions about symmetric hemispheric geometry which are not applicable in FMR, (2) considerations for the continuous-wave Doppler beam angle relative to its interaction with the PISA interface, (3) potential for overestimating EROA when visualization of the flow convergence is suboptimal, (4) inaccurate measurements because of translational and rotational movement of the heart and EROA, and (5) poor reproducibility.2,18,29–31 Furthermore, as a static measurement, the timing for selecting the most appropriate PISA during systole is critical for the calculation of EROA because, as previously noted, its largest radius may not correlate temporally with the peak regurgitant velocity in patients with FMR.6,8 Thus, despite consistent findings among a variety of studies focused on defining temporal variations in the pattern of MR, many methods used for evaluating these dynamic changes have important limitations.
Although the results of our studies are consistent with earlier investigations regarding differences between FMR and DMVD in the dynamic nature of MR, we used a novel approach that used directly measured VCA as a surrogate of EROA. The VCA represents the short-axis area of the MR jet and is conventionally obtained in a consistent manner 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.2,17,32 Consequently, although the use of PISA to calculate EROA in patients with eccentric jets has been scrutinized in the literature, VCA may more accurately reflect the defect on MV leaflet malcoaptation, even when the MR jet is eccentric.33 Because 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 rather than an anatomic EROA.34,35 The VCA like PISA manifests as an asymmetric, crescent shape in FMR compared with organic MR and consequently has been used extensively as a comparative technique for evaluating PISA.3,36–38 Furthermore, the VCA has been historically validated against nonechocardiographic techniques, including ventriculography and MRI in the assessment of MR severity.39,40 Thus, the VCA has several advantages as a comparative measure of EROA and MR severity.
The use of VCA requires the recognition of certain important considerations. For example, high velocity of fluid within the core jet entrains additional fluid from the periphery, thus causing the visible jet seen with color Doppler to appear expanded.16 However, any error in the VCA measurement because of entrainment should not interfere with the relative differences in the temporal patterns observed in patients with FMR compared with DMVD. The VCA has also been shown to be potentially susceptible to pixelation and inaccuracies because of extremes in both color and gray gain settings associated with variability in acquisition and measurement techniques.12,16,17 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 scales gain at the 50% levels.17,18 Nonetheless, although the VCA may have some limitations for use in routine practice, it still may represent the most current ideal quantitative parameter for assessing temporal patterns of MR based on its practical value, as well as previous robust support in the literature as a historical comparison with other nonechocardiographic techniques and as a validation technique for evaluating EROA.
Certain limitations relevant to this study are worthy of further consideration. Because we are not aware of any other published studies specifically addressing our technique for comparisons of directly measured 3D VCAs, the derived effect size used in the power analysis was based on currently available related, yet limited literature,6–12 and current guideline recommendations regarding the specific value which best represents a significant difference between clinically relevant grades of MR severity.2,18 In addition, patients with atrial fibrillation were excluded from the study because of the negative impact of dysrhythmias on the spatial and temporal resolution of full-volume 3D echocardiographic images. However, there is no reason to believe that patients with atrial fibrillation would have a different temporal MR profile. Our patient population also included only those with a single primary MR jet. Although VCA recently has been identified as being a more accurate technique compared with 2D vena contracta width for measuring total EROA in patients with multiple jets, expectations for using multiple 2D or 3D PISAs for this purpose may be impractical and unrealistic.40,41 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, ECG-gated 3D data sets from 14 sequential heart beat 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 from real-time images where volumes rates are frequently <20 Hz.36,37 Finally, some investigators have reported challenges in obtaining reproducible measurements of certain echocardiographic parameters for measuring MR severity.31 The high interobserver reliability that we observed is likely because of our investigators’ significant experience with the software used to perform the quantitative analyses to acquire VCA.
The echocardiographic evaluation of MR remains an essential component of the comprehensive review of patients with suspected valvular heart disease. Although the echocardiographic grading of MR severity usually focuses on determining the extent of the MR jet, degree of the regurgitant volume, and size of the EROA, the temporal pattern of MR throughout the systolic phase of the cardiac cycle is usually not emphasized as a primary focus of clinical interest. Using VCA as a well-validated, direct measure of the dynamic MR orifice area, we have demonstrated not only that EROA varies significantly throughout systole but that these temporal patterns are dependent on the etiology and mechanism of leaflet malcoaptation in patients with FMR compared with those with DMVD. Further investigation is warranted to determine the implications of these dynamic patterns of MR on echocardiographic assessment of MR severity.
Name: Frederick C. Cobey, MD, MPH, FASE.
Contribution: This author is the first author of the manuscript.
Attestation: Frederick C. Cobey attests to the integrity of the original data and the analysis reported in this manuscript. Frederick C. Cobey approved the final manuscript.
Conflicts of Interest: None.
Name: Elena Ashihkmina, MD, PhD.
Contribution: This author helped in primary data collection, data analysis, and preparation of the manuscript.
Attestation: Elena Ashihkmina attests to the integrity of the original data and the analysis reported in this manuscript.
Conflicts of Interest: None.
Name: Thomas Edrich, MD.
Contribution: This author helped in data analysis and preparation of the manuscript.
Attestation: Thomas Edrich attests to the integrity of the original data and the analysis reported in this manuscript.
Conflicts of Interest: None.
Name: John Fox, MD.
Contribution: This author helped in preparation of the manuscript.
Attestation: John Fox attests to the integrity of the original data and the analysis reported in this manuscript.
Conflicts of Interest: None.
Name: Douglas Shook, MD.
Contribution: This author helped in preparation of manuscript.
Attestation: Douglas Shook attests to the integrity of the original data and the analysis reported in this manuscript. Douglas Shook is the archival author.
Conflicts of Interest: Douglas Shook received honoraria related to education from Edwards Lifesciences, Sorin Group, and St. Jude.
Name: Bruce Bollen, MD.
Contribution: This author helped in preparation of manuscript.
Attestation: Bruce Bollen attests to the integrity of the original data and the analysis reported in this manuscript.
Conflicts of Interest: None.
Name: Janis L. Breeze, MPH.
Contribution: This author helped in statistical analysis.
Attestation: Janis L. Breeze attests to the integrity of the original data and the analysis reported in this manuscript.
Conflicts of Interest: None.
Name: Wannakuwatte Waduge Sanouri Ursprung, PhD.
Contribution: This author helped in statistical analysis.
Attestation: Wannakuwatte Waduge Sanouri Ursprung attests to the integrity of the original data and the analysis reported in this manuscript.
Conflicts of Interest: None.
Name: Stanton K. Shernan, MD, FAHA, FASE.
Contribution: This author helped in collection and analysis of data and preparation of the manuscript.
Attestation: Stanton K. Shernan attests to the integrity of the original data and the analysis reported in this manuscript. Stanton K. Shernan is the archival author and approved the final manuscript.
Conflicts of Interest: Stanton K. Shernan is an editor (www.e-echocardiography.com) and an educator (Philips Healthcare, Inc.).
This manuscript was handled by: Martin London, MD.
a Reference 7, Figure 3 demonstrates a range of differences between peak and nadir normalized EROA for FMR patients of 0.7 to 0.9 cm2. Reference 6, Figure 5 demonstrates a range of differences between FMR and DMVD EROAs during early, mid-, and late systole from 0.5 to >1.0 cm2, while current guidelines regarding the identification of differences between clinically relevant grades of MR severity (References 2 and 18) recommend values of ≥0.2 cm2.
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