Tricuspid annular area and leaflets stretch are associated with functional tricuspid regurgitation – insights from three-dimensional transesophageal echocardiography –

The presence of functional tricuspid regurgitation (TR) is associated with mortality and morbidity. Although uniform management with a tricuspid annuloplasty ring is currently considered as a standard surgical procedure, high rates of residual TR despite annuloplasty are reported. Therefore, the identification of the TR mechanisms would be necessary to provide personalized treatment for each TR patient. This study population consisted of 106 patients with mitral regurgitation (MR) who were scheduled for procedure. Transthoracic and transesophageal echocardiography were performed prior to mitral valve intervention. We performed three-dimensional quantitative assessment including tricuspid annular (TA) area and the distance between the three commissures of tricuspid valve. Significant TR, which is defined as moderate or greater TR, was detected in 23 (22%). TA area (P < 0.01), the distance of septal-leaflet length (SL) (P = 0.03) and posterior-leaflet length (PL) (p = 0.02) were significantly associated with significant TR, while TA diameter assessed by transthoracic echocardiography was not. When patients were divided into four groups according to SL and PL, the group with longer SL and PL had a significantly higher incidence of significant TR (P < 0.01). Greater stretch of the septal and posterior leaflet between commissures and larger TA area are associated with significant TR in patients with severe MR. In order to prevent TR recurrence, the intervention of the septal leaflet in tricuspid annuloplasty may be beneficial. The precise implement of three-dimensional transesophageal echocardiography of tricuspid valve is valuable for a personalized strategy of tricuspid annuloplasty.


Introduction
Recognition of the strong association between functional tricuspid regurgitation (TR) and prognosis has implications in treatment of tricuspid valve (TV) disease [1][2][3].Detailed understanding of TV leaflet structure is needed to improve outcomes of transcatheter and surgical TV repair [4].
The most common cause of functional TR is left-sided valvular disease, especially mitral regurgitation (MR).The mechanisms underlying functional TR are tricuspid annular (TA) dilation and leaflet tethering that result in coaptation defects [5,6].Tricuspid annuloplasty is recommended when left-sided valve surgery is needed in patients with significant functional TR, tricuspid annular dilation and prior symptoms of right-sided heart failure [7], however, significant residual TR after tricuspid annuloplasty remains in 10-45% of patients [5,8].
Three-dimensional transesophageal echocardiography (3D TEE) can visualize the entire TV, including the tricuspid annulus, tricuspid valve leaflets, and subvalvular tissue, from various angles, and has been recognized as a useful tool for a detailed understanding of the pathophysiological mechanisms of various TV diseases [4,9].In recent years, 3D TEE has made it possible to observe and analyze the leaflets of the tricuspid valve in detail, and studies using 3D TEE have reported that the characteristics of functional TR associated with atrial fibrillation (AF) are different from those of functional TR associated with left-sided valvular disease [9].
However, little is currently known about the association between moderate or greater degree of functional TR and TV leaflet parameters in patients with severe MR.We hypothesized that if we could clarify the pathogenesis of functional TR considering the characteristics of TV leaflet, we could provide not only uniform management as currently practiced, but also appropriate treatment for each TR patient, leading to improved prognosis.In present study, we assessed to elucidate the relationship between moderate or greater degree of TR in patients with severe MR and TV leaflet parameters using 3D TEE.

Study population
This retrospective single-center cross-sectional study examined consecutive patients with MR who were scheduled for open surgical or transcatheter mitral valve repair at Osaka Metropolitan University Hospital between April 2014 and June 2019.All patients underwent two-dimensional transthoracic echocardiography (TTE) and 3D TEE before the procedure.Those with inadequate 3D TV visualization or moderate or severe aortic valve disease were excluded from analysis (n = 11).Informed consent was obtained using an opt-out approach in this study.The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and the study protocol was approved by the Ethical Committee of Osaka City University Graduate School of Medicine (Approval Number: 2021-064).

Transthoracic echocardiography measurement
Comprehensive TTE was performed with one of the following systems using a high-frequency transducer: EPIQ CVx (Philips Medical Systems, Andover, MA, USA), iE33 (Phillips Medical Systems), Vivid E9 (GE Healthcare, Milwaukee, WI, USA), or Aplio 500 (Canon Medical Systems, Tochigi, Japan).Left ventricle end-diastolic diameter, left ventricular end-systolic diameter, interventricular septum thickness, and posterior wall thickness were measured according to 2017 European Society of Cardiology/European Association for Cardiothoracic Surgery guidelines [10].Left atrial volume and left ventricular ejection fraction (LVEF) were evaluated using the biplane modified Simpson method; left atrial volume was indexed for body surface area [11].The severity of MR was evaluated using a multiparametric approach that included assessment of the vena contracta, effective regurgitant orifice area (determined using the proximal isovelocity surface area method), and Dopplerderived regurgitant volume [12].Severe MR was defined as effective regurgitant orifice area ≥ 0.40 cm 2 , regurgitant volume ≥ 60 mL, or regurgitant fraction ≥ 50% [7].TR severity was evaluated using a multiparametric assessment of jet size, jet eccentricity, and vena contracta of the right ventricular (RV) inflow on parasternal short-axis and apical four-chamber views [13].Significant TR was defined as moderate or severe TR.Peak TR jet velocity was measured from the cardiac apex.TR pressure gradient (TRPG) was calculated using the simplified Bernoulli equation and RV diameter was measured on an RV-focused four-chamber view at the base and mid-cavitary levels [14].

Three-dimensional transesophageal echocardiography measurement
TEE was performed under intravenous propofol sedation with the iE33 or EPIQ CVx system (Philips Medical Systems, Andover, MA, USA) using a matrix-array transducer (X7-2t transducer and X8-2t transducer, Philips Medical Systems, Andover, Massachusetts, USA).Volume data sets were obtained using the live 3D zoom mode or 4-beat fullvolume mode focused on the TV.Images were optimized for depth and gain settings before 3D acquisition.In patients with AF, live 3D zoom mode was selected to avoid stitch artifact and volume acquisition was performed for one beat [15].All 3D TEE data were digitally stored for off-line analysis.TV parameters were acquired from the 3D reconstruction images of the TV annulus and analyzed using commercially available software (QLAB 3DQ and MVQ, Philips Medical Systems, Andover, MA, USA).

Analysis of TV annulus and leaflets and morphology
3D data were displayed in the en face view with the interatrial septum positioned inferiorly (6 o'clock position), regardless of the orientation of the atria and ventricles (Fig. 1A) [16].3D parameters of the TV annulus were measured using QLAB mitral valve quantification software (QLAB MVQ, Philips Medical Systems, Andover, MA, USA).All three commissures between each three leaflets were detected (Fig. 1B).TA intercommissural distances, which are between the anteroseptal, anteroposterior, and posteroseptal commissures of the TV were also measured [9,17,18].The distance between the anteroseptal and posteroseptal commissures, anteroseptal and anteroposterior commissures, and anteroposterior and posteroseptal commissures was defined as septal-leaflet length (SL), anterior-leaflet length (AL), and posterior-leaflet length (PL), respectively (Fig. 1C).

Statistical analysis
Continuous variables are expressed as medians with interquartile range.(IQR) and were compared using the unpaired t-test or Mann-Whitney U test as appropriate.Categorical variables are expressed as numbers with percentage and were compared using the χ2 test or Fisher's exact test.Receiver operating characteristic (ROC) curve analysis was used to determine diagnostic performance of SL and PL for predicting significant TR.The appropriate cut-off value was selected to maximize the (sensitivity + [1 − specificity]) value.Inter-and intra-observer variabilities of 3D TEE annulus and distance measurements were evaluated by analysis of measurements in 20 random cases using the intraclass correlation coefficient.For interobserver variability, measurements were performed by two independent blinded observers; for intraobserver variability, measurements were performed by the same observer at two different time points.P < 0.05 was considered significant.Statistical analyses were performed using open source EZR software.

Results
Among the 106 patients with severe MR who were scheduled for either surgery or transcatheter mitral valve repair, Moderate or greater degree of TR was detected in 23 cases (22%).There were 18 patients with moderate TR and 5 patients with severe TR shown in Fig. 2. Patient characteristics and TTE data are shown in Table 1.Median patient age was 68 years (IQR, 58-76) and 55 (51.9%) were men.AF was present in 46 patients (43.4%) and 83 (78.3%) had Mitral valve prolapse.Median LVEF was 63% (IQR, 60-65%).Median left atrial volume index was 62.8 ml/m 2 (IQR, 47.7-84.2).Median TA diameter was 33.9 mm (IQR, 30.1-36.9).Median TR pressure gradient was 24 mm Hg (IQR, 20.5-28).The patients could be divided into two groups according to whether significant TR group (moderate or greater degree of TR, 23/106, 22%) or non-significant TR group (mild or less degree of TR, 83/106, 78%).Clinical baseline characteristics and TTE data of the two groups were shown in Table 1.Estimated glomerular filtration rate, EF, and TA diameter did not differ between the two groups.In the significant TR group, the proportion of patients with AF was significantly higher (73.9% vs. 34.9%;P < 0.01) and the proportion of patients with mitral valve prolapse was significantly lower (52.5% vs. 85.5%;P < 0.01).In addition, left atrial volume index (91 vs. 57.2;P < 0.01) and TRPG (37 vs. 23 mm Hg; P < 0.01) were significantly higher in the significant TR group.
The parameters of tricuspid valve and annulus derived from 3D TEE were listed in Table 2. TA area was significantly larger in the significant TR group than the nonsignificant TR group (1154.1 vs. 987.9mm²; P < 0.01).Furthermore, SL (30.8 vs. 28.0mm; P = 0.03) and PL (31.9 vs. 28.1 mm; P = 0.02) were significantly longer in the significant TR group.When all patients were divided into 4 groups according to longer SL and longer PL in tricuspid valve leaflet, the group longer SL (SL > 26.8 mm, which is the optimal value identified by ROC analysis, AUC 0.65) and longer PL (PL > 30.8 mm, which is the optimal value identified by ROC analysis, AUC 0.66) had higher incidence of significant TR (P < 0.01) (Fig. 3; Table 3).

Discussion
The key findings of this study of patients with severe MR scheduled for mitral valve repair were as follows: (1) 22% of patients also had moderate or severe TR (significant TR); (2) There was no significant difference in TA diameter measured on TTE, however, 3D TEE analysis demonstrated that TA area was significantly greater, and SL and PL  effectively [27,28].Additionally, Peng T et al. reported that the septal leaflet length has a higher sensitivity to functional TR recurrence after annuloplasty than that of the anterior or posterior leaflet [24].In order to prevent TR recurrence, the intervention of not only anterior and posterior leaflet but also septal leaflet in tricuspid annuloplasty, such as the additional septal annulus plication, may be beneficial.Detailed preoperative analysis of the TV leaflet using 3D TEE may play an important role in determining which patients need leaflet augmentation.

Limitations
This study has several limitations.First, this was a retrospective single-center observational study that included only Japanese patients with severe MR.A control group was not examined.Therefore, future prospective studies with controls are necessary to definitively assess the association between moderate or severe TR and TV leaflets.Second, selection bias may have been introduced because our study population consisted of patients who were referred for treatment of severe MR.Third, significant TR group had a higher proportion of patients with AF, suggesting that TV dilation could be affected by AF.In this study, it is difficult to determine clearly whether the TV dilation is due to leftsided valvular disease or AF.Fourth, although interobserver reliability was high, our findings may not be generalizable as advanced technique is required to acquire accurate 3D TEE images.It is important to gradually make appropriate changes in gain settings, probe depth, angle, focus distance, and sizing of area of interest to improve 3D TV imaging.
Fifth, the posterior leaflet of the TV might have multiple scallops.In this study, we could not take a consideration completely because accurate evaluation of the number of leaflets needs high-quality 3D TEE images.Finally, we did not conduct clinical and echocardiographic follow-up.

Conclusion
Greater stretch of the septal and posterior leaflet between commissures and larger TA area were associated with significant TR in patients with severe MR.In order to prevent TR recurrence, the intervention of the septal leaflet in tricuspid annuloplasty can be valuable.3D TEE enables detailed observation of TV leaflet morphology in addition to annular diameter.Careful assessment of morphologic variations of tricuspid valve makes personalized strategy of tricuspid annuloplasty, which may lead to a prevention of residual TR after surgery.
Author contributions All authors contributed to the study conception and design.Material preparation, data collection and analysis were were significantly longer in patients with significant TR; (3) Patients with SL > 26.8 mm and PL > 30.8 mm had a significantly higher incidence of moderate or severe TR.
Previous studies have reported that more than 30% of patients with severe MR also have moderate or severe TR [17,19].In this study, there were 23 patients (22%) with moderate or greater degree of TR.The reason for the lower frequency of FTR concomitant with severe MR compared to previous studies is that approximately 80% of patients had MV prolapse with preserved EF in this study because early intervention for severe MR with MV prolapse improved prognosis [20,21].Our study shows that significant functional TR concomitant with severe MR is associated with TA area, SL, and PL as assessed by 3D TEE, but not TA diameter as measured by TTE as recommended by guidelines [7].While one previous study examined annular and subvalvular geometry as determinants of functional TR [22], another demonstrated that remodeling of the TV leaflet plays an important role in functional TR pathophysiology [23].Afilalo et al. showed that the severity of TR increases when the TV leaflet area is inadequate to cover the closure area; they concluded that the balance between leaflet adaptation and annular expansion is a strong indicator of functional TR severity [23].Our study showed that moderate or severe TR in patients with severe MR is associated not only with enlargement of the TV annulus but also with elongation of the posterior and septal leaflets.Differences in the degree of elongation of each leaflet may affect the degree of TR because of the poor balance between leaflet adaptation and annular expansion.A detailed evaluation of each leaflet of TV has rarely been reported, this study clarified that the mechanism of TR requires not only TV annulus enlargement but also the balance between the degree of enlargement of each leaflet of TV.Peng T et al. demonstrated that each leaflet, including septal leaflet, is dilated with an increase in FTR severity by direct intraoperative assessment of TA dilation in functional TR [24], which is consistent with our findings from an echocardiographic perspective.
Besides the implications regarding the mechanism, our findings may be clinically important for functional TR repair.TV annuloplasty is currently recommended as an effective treatment and associated with improved long-term outcomes [25,26].However, the rate of early residual TR is higher than expected [5,8].Because TV annuloplasty only addresses annular dilation especially for anterior and posterior leaflet, the observation that other factors would be predictors of TR recurrence is unsurprising.Our findings indicate that inadequate leaflet coaptation may be one important predictor of TR recurrence.In fact, several previous studies have reported lower TR recurrence rates when the TV is augmented using autologous pericardial patches during annuloplasty to enlarge the anterior tricuspid leaflet

Fig. 2 Fig. 1
Fig. 2 Prevalence of TR before mitral valve intervention.In all 106 patients with mitral regurgitation, Moderate or greater TR was detected in 23 cases (22%)

Fig. 3 Table 2
Fig.3The combination of septal-leaflet length and posterior-leaflet length to predict significant TR with severe MR patients.MR, mitral regurgitation; ROC, receiver operating characteristic; TR, tricuspid regurgitation

Table 1
Baseline characteristics and TTE data of the study population

Table 3
The cut-off value of leaflet length for predicting moderate or greater TR with severe MR patients