Echocardiographic insights into atrial and ventricular mechanisms of functional tricuspid regurgitation

Valvular and Congenital Heart Disease

Echocardiographic insights into atrial and ventricular mechanisms of functional tricuspid regurgitation Shota Fukuda, MD,a A. Marc Gillinov, MD,b Jong-Min Song, MD,a Masao Daimon, MD,a Vorachai Kongsaerepong, MD,a James D. Thomas, MD,a and Takahiro Shiota, MDa Cleveland, OH

Background The etiology of functional tricuspid regurgitation (TR) is thought to be annular dilatation and tethering of tricuspid valve (TV) leaflets. However, mechanisms of leaflet tethering are incompletely understood. The purpose of this study was therefore to investigate the relationships between TV annular dilatation and leaflet tethering with the severity of functional TR and to investigate factors that influence these TV deformations. Methods Two hundred forty-five patients with functional TR had 2-dimensional echocardiography. Echocardiographic investigations focused on the ventricles and on the TV. Ventricular measurements included left ventricular (LV) volume, right ventricular (RV) area, and RV spherical index. Valvular measurements included systolic TV annular dimension and apical displacement (tethering height), as well as severity of TR (vena contracta width). Results

Tethering height (r 2 = 0.25) was related to the severity of TR ( P b .001). The RV and right atrium areas influenced both annular dimension and tethering height. However, LV ejection fraction and RV spherical index affected tethering height but not annular dimension.

Conclusions

Tethering of TV leaflets, a determinant of functional TR, is associated with changes in right-sided cavity size as well as RV sphericity and LV function, emphasizing the impact of changes in ventricular geometry and function on the severity of functional TR. (Am Heart J 2006;152:1208214.)

Functional tricuspid regurgitation (TR) is an important complication of left-sided valvular heart lesions, and it frequently persists after mitral and aortic valve operations, contributing to increased morbidity and mortality.1-3 Consequently, tricuspid valve (TV) annuloplasty is now widely used for surgical management of functional TR in patients having surgery for left-sided heart disease even if significant residual regurgitation persists or recurs in 10% to 20% after annuloplasty.4-6 To overcome the limitations of current surgical techniques for functional TR, there is a need for better understanding of the mechanism of TV deformations. Previous studies demonstrate that annular dilatation and leaflet tethering contribute to the development of functional TR.7-12 We have shown that the degree of preoperative tethering of the TV leaflets is associated

From the

a

Department of Cardiovascular Medicine, Cleveland Clinic Foundation,

Cleveland, OH, and bDepartment of Thoracic and Cardiovascular Surgery, Cleveland Clinic Foundation, Cleveland. Disclosures: Dr Gillinov has served as consultant to Edwards Lifesciences, LLC. Submitted March 24, 2006; accepted July 13, 2006. Reprint requests: Takahiro Shiota, MD, Department of Cardiovascular Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F15, Cleveland, OH 44195. E-mail: [email protected] 0002-8703/$ - see front matter n 2006, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2006.07.027

with residual TR after annuloplasty.6 However, in contrast to the wealth of information linking functional mitral regurgitation to the left ventricle (LV), there is little information focusing on the impacts of LV and right ventricular (RV) function and geometry on TV function and geometry. The TV annulus is located between the RV and the right atrium (RA), and its papillary muscle is attached to the RV free wall and interventricular septum, suggesting that processes that impact the RV might affect the TV. In addition, geometric and/or functional changes of the LV may augment TV annular dilatation and/or tethering because of ventricular interdependence transmitted from the LV to RV through the interventricular septum, pericardium, or circulatory effects.13-17 The purpose of this study was to clarify the relationships between the severity of functional TR and TV annular size and tethering and to investigate the factors that influence these TV deformations, with particular emphasis on the impacts of LV and RV.

Methods Patients A total of 384 consecutive patients with functional TR who had transthoracic 2-dimensional echocardiography initially enrolled from the Cleveland Clinic Foundation echocardiography database, which was approved by the Institutional Review Board for clinical research. Functional TR was defined as

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Figure 1

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Table I. Echocardiographic results in patients with functional TR and in controls Patients with TR LV EDV (mL) LV ESV (mL) LV long-axis dimension (cm) LV EF (%) LV spherical index RV systolic area (cm2) RV long-axis dimension (cm) RV FAC (%) RV spherical index RA area (cm2) RV systolic pressure (mm Hg) TV annular dimension (cm) TV tethering height (mm) TR severity (VCW, mm)

181.2 103.0 7.1 46.8 15.0 16.6 6.3 29.9 2.5 24.7 53.7 3.8 6.7 6.2

F F F F F F F F F F F F F F

87.1 73.9 1.3 14.7 11.7 7.1 1.3 12.0 0.7 9.3 17.7 0.7 4.2 3.1

Controls 101.9 38.5 6.5 63.1 9.3 6.5 4.0 47.5 1.6 12.8

F F F F F F F F F F

38.4 22.2 1.2 10.8 4.1 2.5 0.8 10.4 0.4 5.1

2.5 F 0.5 1.6 F 1.0

P b.001 b.001 .003 b.001 b.001 b.001 b.001 b.001 b.001 b.001 b.001 b.001

(1) N2+ TR on the clinical echocardiographic report based on a scale of 0 to 4+, (2) without any organic TV diseases, and (3) no history of prior TV surgery. Patients with congenital heart disease (n = 35), pacemaker wires across the TV (n = 66), cardiac tamponade (n = 13), and poor image quality on echocardiography (n = 25) were excluded. The final population consisted of 245 patients (age, 20-94 years; mean, 67 F 13 years; 87 men). All patients had left-sided valve disease or LV systolic dysfunction (ejection fraction [EF], b40%) in this study. In addition, no patient had evidence of primary RV disease, such as arrhythmogenic RV cardiomyopathy. Aortic valve disease was present in 35 patients (14%), mitral valve disease in 138 (56%), and both aortic and mitral valve diseases in 55 (22%). Aortic or mitral valve disease was defined as moderate or severe regurgitation, stenosis or both, according to the clinical echocardiographic report. A history of coronary artery disease was observed in 94 (38%) patients, atrial fibrillation in 50 (20%), history of prior sternotomy in 84 (34%), and pulmonary hypertension (RV systolic pressure N40 mm Hg) in 185 (76%). In addition, 50 patients (mean age, 67 F 12 years; 36 men) with no more than physiologic TR and no significant left-sided valvular disease on echocardiography were served as agematched controls. These patients were used to establish the normal values for RV spherical index, annular dilatation, and tethering of the leaflet.

MA), Vivid 7 (GE Medical Systems, Milwaukee, WI), or Sequoia 512 (Siemens, Mountainview, CA) echo system. Echocardiographic images were obtained in standard parasternal and apical views and analyzed offline. After carefully choosing the highest possible quality image using our digital storing system, echocardiographic measurement was done with the best frame in patients with sinus rhythm. The values of echocardiographic parameters were averaged over 5 cardiac cycles in patients with atrial fibrillation. The LV end-systolic volume (ESV) and end-diastolic volume (EDV) were obtained to calculate LV EF using Simpson’s method from apical 4- and 2-chamber views.18 LV spherical index was defined as the LV ESV divided by the LV longest axis dimension in the apical 4-chamber view. Systolic and diastolic RV areas were measured by planimetry, tracing the endocardial outline of the RV and the plane of the TV in the apical 4-chamber view; RV fractional area change (FAC) was calculated from these measurements.19,20 Systolic RV area was then divided by RV long-axis dimension (measured from the tip of the true RV apex to the midpoint of TV annular plane) to calculate the RV spherical index. Minimal TV annular dimension and tethering height were also measured in the apical 4-chamber view (Figure 1) as previously described.6 The severity of TR was estimated by the vena contracta width (VCW) as previously reported.21,22 The color Doppler image was obtained from apical 4-chamber view, and the mean value of the aliasing velocity was 58 F 5 cm/s, ranging from 38 to 77 cm/s. Vena contracta width was measured at midsystole as the distance of the narrowest neck of regurgitation jet just distal to the flow convergence region. Holosystolic flow was observed in all patients except in 2. In these 2 patients with late-systolic flow, VCW measurement was done at late systole. Right ventricle systolic pressure was estimated by the simplified Bernoulli equation,23 adding the RA pressure estimated from the diameter of the inferior vena cava during respiration as previously described by Otto.24,25

Transthoracic 2-dimensional echocardiography

Statistical analysis

Transthoracic 2-dimensional echocardiography was performed with a Sonos 5500 (Philips Medical Systems, Andover,

Values were expressed as mean F SD or percentages. Groups were compared with unpaired t test. Linear regression

An apical 4-chamber view demonstrating techniques for measuring TV deformations. The TV annular dimension (dashed line) and tethering height (solid line) were determined by the distance between the tips of the arrowhead, respectively. LA, Left atrium.

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Table II. Relationship of echocardiographic parameters with TV severity

LV EDV LV ESV LV long-axis dimension LV EF LV spherical index RV systolic area RV long-axis dimension RV FAC RV spherical index RA area RV systolic pressure TV annular dimension TV tethering height

r2

Univariate P

0.003 b0.001 b0.001 0.003 b0.001 0.16 0.08 b0.001 0.17 0.19 0.006 0.12 0.20

.4 .9 .9 .4 .9 b.001 b.001 .9 b.001 b.001 .2 b.001 b.001

Figure 3

Multivariate P

.2 .1 .03 b.001 .6 b.001

Figure 2

Regression plots showing correlations between the severity of TR and annular dimension. Patients were divided into 2 groups according to the presence or absence of significant tethering.

Regression plots showing correlation between annular dimension and tethering height.

analysis was used for correlation of variables of interest. Multivariate stepwise linear regression analysis was performed to identify determinant factors, and significant variables on univariate analysis were entered into models. Differences were considered significant at P b .05. Inter- and intraobserver variabilities for measurement of VCW, annular dimension, and tethering height were determined by analysis of 10 random images by 2 independent blinded observers and by the same observer at 2 different time points. The results were analyzed by both least squares fit linear regression analysis and the Bland-Altman method.26

Results Characteristics Echocardiographic results in patients with TR and in controls were summarized in Table I. Relationship between TR severity and echocardiographic parameters In the univariate analysis, TR severity (VCW) was correlated with RV systolic area, RV long-axis dimension, RV spherical index, RA area, TV annular dimension, and

tethering height as shown in Table II. When these 6 parameters were entered into the stepwise multivariate regression analysis, RV spherical index ( P = .03), RA area ( P b .001), and tethering height ( P b .001) were significant factors. In univariate analysis, annular dimension was weakly correlated with tethering height (r 2 = 0.20; P b .001) (Figure 2).

Tricuspid valve deformations and TR severity Patients were divided into 2 subgroups according to the presence or absence of significant annular dilatation and tethering of the leaflet, respectively. Cutoff values were 3.5 cm for annular dimension and 3.6 mm for tethering height. These values were chosen as the mean value F 2SD in the measurement of control group. In 245 patients, significant annular dilatation was observed in 96 (39%) patients and tethering of the leaflet in 63 (26%) patients. In patients without tethering of the leaflet, there was no significant correlation between TR severity (VCW) and annular dimension (r 2 = 0.05; P = .08), whereas TR severity weakly but significantly related to annular dimension in patients with tethering of the leaflet (r 2 = 0.10; P b .001) (Figure 3). On the other hand, similar correlations between TR severity and tethering height were observed in patients with (r 2 = 0.22; P b .001) and without annular dilatation (r 2 = 0.19; P b .001) (Figure 4).

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Figure 4

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Table III. Relationship of echocardiographic parameters with TV annular dimension

LV EDV LV ESV LV long-axis dimension LV EF LV spherical index RV systolic area RV long-axis dimension RV FAC RV spherical index RA area RV systolic pressure

r2

Univariate P

Multivariate P

0.07 0.08 0.005 0.03 0.07 0.41 0.26 0.02 0.37 0.36 0.002

b.001 b.001 .3 .01 b.001 b.001 b.001 .02 b.001 b.001 .5

.5 .4 .9 .4 b.001 .5 .009 .3 b.001

Table IV. Relationship of echocardiographic parameters with tethering height

Regression plots showing correlations between the severity of TR and tethering heights. Patients were divided into 2 groups according to the presence or absence of significant annular dilatation of the leaflet, respectively.

Determinants of annular dimension By univariate analysis, RA area and 8 indices of RV and LV geometry and function were correlated with TV annular dimension (Table III). When all 9 significant parameters by univariate analysis were included in the stepwise multivariate regression analysis, RV systolic area ( P b .001), RV FAC ( P = .009), and RA area ( P b .001) were significantly correlated with TV annular dimension (Table III). Determinants of tethering height As with annular dimension, by univariate analysis, RA area and 8 indices of RV and LV geometry and function were related to TV tethering height (Table IV). Among these 9 indices, by the stepwise multivariate regression analysis, LV EF ( P = .008), RV systolic area ( P b .001), RV spherical index ( P = .03), and RA area ( P = .004) were identified as independent factors correlated with TV tethering height (Table IV). Impact of the etiology of left-sided lesion on TR severity and TV deformations The presence of aortic or mitral valve disease, the history of coronary artery disease, or atrial fibrillation did not affect on the degree of TR severity, annular dimension, and tethering height as shown in Table V.

LV EDV LV ESV LV long-axis dimension LV EF LV spherical index RV systolic area RV long-axis dimension RV FAC RV spherical index RA area RV systolic pressure

r2

Univariate P

Multivariate P

0.10 0.15 0.002 0.11 0.14 0.42 0.37 0.08 0.29 0.18 b0.001

b.001 b.001 .6 b.001 b.001 b.001 b.001 b.001 b.001 b.001 .9

.6 .6 .008 .3 b.001 .7 .6 .03 .004

However, patients with history of prior sternotomy had greater TR severity ( P = .04) and larger tethering height ( P = .01) than those without history of prior sternotomy, whereas there was no significant difference in annular dimension.

Observer variability Excellent correlation was observed in interobserver and intraobserver variability of echocardiographic measurements. Values were r 2 = 0.92 and r 2 = 0.92 for VCW, r 2 = 0.86 and r 2 = 0.85 for annular dimension, and r 2 = 0.83 and r 2 = 0.71 for tethering height. From the BlandAltman method, inter- and intraobserver variabilities were 0.5 and 0.5 mm for VCW, 0.16 and 0.08 cm for annular dimension, and 3.2 and 1.3 mm for tethering height.

Discussion Key findings This study emphasizes the importance of leaflet tethering on the pathogenesis of functional TR. Tethering of the TV leaflets is sufficient to cause TR even in the absence of significant TV annular dilatation. Tethering of

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Table V. Relationship between clinical characteristics and TR severity and TV deformations TR severity (VCW, mm) Aortic valve disease

+

Mitral valve disease

+

Coronary artery disease

+

Atrial fibrillation

+

Prior sternotomy

+

6.3 6.2 6.1 7.1 6.3 6.2 6.5 6.2 6.9 5.9

F F F F F F F F F F

3.2 3.1 2.8 4.3 3.5 2.8 2.5 3.3 3.6 2.8

P .9 .1 .6 .5 .04

TV leaflets is associated with changes in right-sided cavity size, RV sphericity, and LV function, demonstrating the impact of changes in ventricular geometry and function on the pathogenesis of functional TR.

Impact of tethering of TV leaflets on the severity of functional TR Previous echocardiographic and angiographic studies reported that RV enlargement caused tricuspid annular deformation and displacement of papillary muscles, leading to inadequate leaflet coaptation in patients with functional TR associated with left-sided disease.7-12 However, the relative importance of annular dilatation and leaflet tethering in the pathogenesis of functional TR is incompletely understood; an understanding of this relationship may influence surgical treatment of functional TR. A recent study from our institution investigated the effect of TV deformations on the early outcome after annuloplasty in patients with functional TR.6 Annuloplasty techniques treated only annular dilatation and did not directly address tethering of the leaflets; the degree of preoperative tethering of the leaflets predicted residual TR after annuloplasty in that study. Although there have been many studies of the mechanisms and determinants of the tethering of mitral valve leaflets in patients with functional mitral regurgitation, these issues have not been studied as widely in functional TR.27-30 In this study, overall correlations between the severity of TR and tethering of TV leaflets were significant. Moreover, this correlation was similarly observed between patients with and without annular dilatation. This result indicates that, although annular dilatation and tethering of the leaflets often coexist in functional TR, tethering of TV leaflets is sufficient to induce regurgitation, even in the absence of significant annular dilatation. Ventricular mechanisms of leaflet tethering in functional TR The present study demonstrated that TV annular dilatation was associated with right-sided cavity

Annular dimension (cm) 3.7 3.8 3.8 3.9 3.8 3.8 4.0 3.8 3.9 3.8

F F F F F F F F F F

0.8 0.7 0.7 0.8 0.7 0.7 0.7 0.7 0.7 0.7

P 0.3 .2 .7 .06 .2

Tethering height (mm) 6.7 6.7 6.6 7.3 6.7 6.7 6.3 6.8 7.7 6.2

F F F F F F F F F F

3.9 4.3 4.0 4.8 4.4 4.0 3.7 4.3 4.3 4.0

P .9 .3 .9 .4 .01

enlargement. Considering the anatomic location of the TV at the junction between the RA and RV, this result was expected. On the other hand, the development of tethering of the TV leaflets was related to changes in RV size and geometry and to LV function. The considerably dilated and remodeled RV might cause incomplete valve closer due to displacement of papillary muscles attached to the anterior and posterior walls of the RV. This observation parallels studies of functional mitral regurgitation, which demonstrate that LV size and sphericity are associated with the degree of regurgitation.27,31,32 Interestingly, the present study demonstrated that LV function was also an independent factor in the etiology of tethering of the leaflets in functional TR, although the relation was weaker (r 2 = 0.11) than those of RV dilatation (r 2 = 0.42) and RV spherical change (r 2 = 0.29). Left ventricle systolic dysfunction might cause tethering of the TV leaflets because of abnormal shifts of the interventricular septum, which is attached to the chordae tendinae of the TV septal leaflet.13,14 In addition, LV dysfunction might induce geometric changes in the RV via interactions that involve the pericardium15,16 or the sulcus between RV and LV.17 Previous studies demonstrate that severe LV systolic dysfunction is a risk factor for residual TR after TV annuloplasty, demonstrating the relationship between the LV and the TV.5,33,34 Our observation that LV dysfunction impacted leaflet tethering but not on the annulus helps to explain the aforementioned results.

Study limitations The primary limitations of this study relate to echocardiographic measurements. First, the study population in this retrospective analysis was from the echocardiography database in our institution, which consisted of clinical examinations wherein we used 2-dimensional echocardiography. Right ventricle chamber volume was technically difficult to determine because of the complex anatomic geometry of this chamber, which precluded precise volume measurements using currently available 2-dimensional imaging techniques. Therefore,

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the present study measured RV and RA areas but did not attempt to assess their volumes. Moreover, a large portion of the RV might not be visualized from the 4-chamber view obtained using 2-dimensional echocardiography. The sphericity index used to measure RV shape might be flawed because the RV was not a sphere. Although 2-dimensional echocardiography is widely used to evaluate RV size and function and RA size in the clinical setting, 3-dimensional imaging techniques might soon enable more accurate quantification of RV volume and function and RA volume.35 Second, in the apical 4-chamber view, only the septal and anterior leaflets were visualized, and these images were used to measure tethering height. Three-dimensional echocardiography will likely enable us to estimate the degree of TV tethering height at each leaflet, which might give further insight into the pathogenesis of functional TR.30 Third, because the severity of TR in the study was quantified by VCW (as a continuous value), the overall TR grade according to the recommendation of the American Society of Echocardiography was not reported.36 Finally, we previously reported that preoperative tethering leaflet was a risk factor of residual regurgitation after TV repair.6 In this study, we demonstrated the association between RV dilatation and tethering of leaflets. It was therefore speculated that in the massively dilated RV, causing tethering of the leaflets, undersized ring annuloplasty may not work for TR as for mitral regurgitation, although this was not proven in this study. In addition, because this study was focused to investigate echocardiographic determinants of TR severity and TV deformations, we did not have any echocardiographic examination after TV repair in the present study. Therefore, the impact of the result in this study on long-term outcome after TV surgery remains to be investigated.

Conclusions Tethering of TV leaflets, a key determinant of functional TR, is associated with changes in right-sided cavity size as well as RV sphericity and LV function. This information provides mechanistic insights into the impact of atrial and ventricular geometry and function on functional TR.

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