Four-dimensional automated quantitative echocardiography assessment of right heart remodeling in patients with functional tricuspid regurgitation

Introduction

Functional tricuspid regurgitation (FTR) is typically associated with morphological changes and dysfunction of the right heart due to various causes. Patients diagnosed with severe tricuspid regurgitation (TR) have a mortality rate of 40% or higher within 3 years (1). The clinical management of patients with severe TR is frequently determined by the dilation of the right ventricle (RV) and the gradual reduction in its function. The right atrium (RA), on the other hand, has only been studied in terms of its dimensions, and functional changes and remodeling have not been the subject of in-depth investigation (2). A recent study used two-dimensional (2D) speckle tracking echocardiography (STE) to assess right atrial reservoir strain (RASr) in patients with FTR (3). However, the clinical application of STE is limited by the thin-walled structure of the RA and the irregular arrangement of myocytes (4).

Four-dimensional (4D) automated quantitative echocardiography is a newly developed analysis technology that is based on three-dimensional (3D) datasets. It can quickly and dynamically reconstruct the heart chambers in three dimensions and analyze them quantitatively using artificial intelligence algorithms. This technology can help accurately assess heart chamber volume and function, improving diagnostic efficiency. One of the techniques, 4D automated left atrial quantification (4D Auto LAQ), provides measure of both longitudinal and circumferential left atrial strain (5). The purpose of this study was to use to 4D automated RV quantification (4D Auto RVQ) and 4D Auto LAQ to comprehensively assess and compare the anatomical characteristics and function of the right heart in healthy adults and patients with varying degrees of FTR. Additionally, we aimed to investigate the correlation between TR volume and various parameters and evaluate the relationship between right heart remodeling and the severity of TR in patients. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-676/rc).

Methods

Study population

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Medical Ethics Committee of The First Affiliated Hospital of Guangxi Medical University (No. 2021-E477-01). All participants signed an informed consent form. Between February 2022 and March 2023, we prospectively and consecutively selected 132 patients who were diagnosed with TR by echocardiography at The First Affiliated Hospital of Guangxi Medical University. To ensure the validity of the findings, strict inclusion and exclusion criteria were applied. The inclusion criteria included patients aged 18 years or older with a confirmed diagnosis of TR, satisfactory quality of 2D and 3D echocardiographic images, and the ability to provide informed consent. In contrast, patients were excluded if they had primary TR, including tricuspid valve (TV) prolapse malformation, rheumatic TV disease, TV prolapse, etc., poor echocardiographic image quality, systemic disorders, or a pregnancy. According to the exclusion criteria, 17 patients with unsatisfactory quality of 2D and 3D echocardiographic images and 15 patients with primary TR were excluded. According to recent guidelines (6-9), 47 patients (47%) with atrial FTR and 53 patients (53%) with ventricular FTR were included. Based on the degree of TR, 50 patients were placed into a mild FTR group, while the remaining 50 cases were placed into a moderate-or-severe FTR group. Additionally, 30 healthy volunteers were selected as the control group (Figure 1).

Figure 1 Patient screening flowchart. TR, tricuspid regurgitation; FTR, functional tricuspid regurgitation.

Echocardiographic measurements

For echocardiographic measurements, the participant was positioned in the left prone position and connected to an electrocardiogram. A Vivid E95 ultrasonic diagnostic instrument (GE HealthCare, Chicago, IL, USA), equipped with a transthoracic real-time 3D 4VC probe (frequency: 1.5–4.0 MHz) was used to conduct a comprehensive 2D and 3D echocardiographic evaluation. To begin, we entered the 2D multiplanar imaging mode and adjusted the cardiac cycle to 3–5 beats (5 beats in patients with persistent atrial fibrillation). We then instructed the participants to hold their breath at the end of expiration and acquired a 2D image set in the four-chamber view of the heart, a TR image using the color Doppler flow imaging mode, and the reflux spectrum using the continuous Doppler mode. We entered the 4D full-volume imaging mode and adjusted the sector size to fully display the cardiac structure. We avoided decreasing the frame rate due to the oversized sector, ensuring that the frame rate was more than 40% of the patient’s heart rate. In the four-chamber view, positioned the RA and RV at the center of the sector to display the TV device completely. The temporal resolution was set to ≥30 volumes/s (≥20 volumes/s in patients with persistent atrial fibrillation). Participants were instructed to hold their breath at the end of expiration. The quality of the image stitching was assessed using MultiSlice to reduce stitching artifacts and obtain a 3D image set. Ultimately, for all 130 participants, were able to obtain complete and clear 2D multicardiac cycle images and 3D full-volume images.

Image analysis

The EchoPAC 204 workstation (GE HealthCare) was used to import 3D full-volume images, which were subsequently evaluated by senior echocardiography fellows. Subsequently, 4D Auto LAQ technology was used to quantify the RA. To do so, the operator needed to place the landmark in the middle of the TV center in “Set Landmark” mode and ensure that the blue line was in the right atrial plane. The position of the landmark could be adjusted by dragging it in each plane. The results could be displayed as a contour in 2D slices and as a model in 3D rendering. This could provide information on RA volume, function, and strain parameters, including the RA maximum volume (RAVmax), RA minimum volume (RAVmin), and right atrial ejection fraction (RAEF). The technique also provided several RA longitudinal strain parameters, including RASr, right atrial conduit strain (RAScd), and right atrial contraction strain (RASct), as well as RA circumferential strain parameters, including right atrial reservoir circumferential strain (RASr-c), right atrial conduit circumferential strain (RAScd-c), and right atrial contraction circumferential strain (RASct-c) (Figure 2A). Additionally, the operator placed the landmark in the TV center in “Set Landmark” mode and ensured that the blue line was in the right ventricular plane. The position of the landmark could be adjusted by dragging it in each plane. The study could display the results as a contour in 2D slices and as a model in 3D rendering. The measurements obtained with 4D Auto RVQ included right ventricular end-diastolic volume (RVEDV), right ventricular end-systolic volume (RVESV), right ventricular ejection fraction (RVEF), and tricuspid annular plane systolic excursion (TAPSE) (Figure 2B). The biplane Simpson method was used to measure the left ventricular ejection fraction (LVEF) from a 2D image set. The TR volume was calculated and assessed for the degree of FTR using various methods recommended by the relevant guidelines (10-13) (Figure 3), and the pulmonary artery systolic pressure was estimated from the TR spectrum (14). The RV globe strain was also measured using STE.

Figure 2 Echocardiographic measurements. (A) Right atrial volume and function parameter landmarks as measured by the 4D Auto LAQ and (B) right ventricular volume and function parameter landmarks as measured by the 4D Auto RVQ. 4D, four-dimensional; 4D Auto LAQ, 4D automated left atrial quantification; 4D Auto RVQ, 4D automated right ventricular quantification.

Figure 3 Cardiac 3D datasets and TR assessment. (A) Cardiac 3D datasets. (B) FTR volume assessment. LV, left ventricular; RV, right ventricular; LA, left atrial; RA, right atrial; TR, tricuspid regurgitation; 3D, three-dimensional; FTR, functional tricuspid regurgitation.

Reproducibility of right heart parameter measurements

The study examined the reproducibility of right heart parameters through intraobserver and interobserver calculations of intraclass correlations and coefficients of variation. Interobserver variability was assessed by two selected observers who evaluated the right heart parameters in 15 patients. Intraobserver variability was obtained by one observer who performed repeated measurements on the same 15 cases studied at 3-week intervals.

Statistical analysis

The data were analyzed using SPSS 25 (IBM Corp., Armonk, NY, USA). Initially, the normality of the data was assessed using the Shapiro-Wilk test. Continuous variables were expressed as the mean ± standard deviation (SD) or as the median with the 25^th to 75^th percentile interquartile range (IQR), while categorical data were presented as numbers and percentages. Differences between the three groups were compared using either one-way analysis of variance (ANOVA) for parametric data or the nonparametric Kruskal-Wallis test. Post hoc analysis was then performed using the least significant difference (LSD) t-test for parametric data or with the Mann-Whitney test for nonparametric data, as appropriate. Pearson linear correlation coefficient was applied to investigate the correlation between various parameters and TR volume. Furthermore, a multivariate linear regression analysis was conducted to identify the factors significantly associated with TR volume. Logistic regression analysis was employed to predict the severity of TR. Statistical significance was set at a two-tailed P value of <0.05.

Results

Clinical characteristics

The clinical characteristics of this study are shown in Table 1. There were no statistically significant differences in age, gender, body surface area (BSA), or systolic blood pressure between the three groups. However, the LVEF was slightly lower in the moderate-to-severe FTR group compared to both the control group and the mild FTR group.

The multiparametric approach to FTR severity is detailed in Table 2. According to recent guidelines (12), among patients with FTR, mild, moderate, severe, massive, and torrential FTR were found in 50, 15, 17, 12, and 6 cases.

Right heart parameters

The comparison of right heart volume and functional parameters among the three groups revealed that patients with FTR had significantly dilated RA volume and decreased RAEF. Patients with more than moderate FTR had increased RV volume and decreased RV functional parameters. However, patients with mild FTR did not show significant dilation of the RV or decreased function (Table 3). According to the relevant guidelines (15,16), almost all patients with FTR had RA dilatation, with significant RV dilatation in patients in the moderate-to-severe FTR group and slight RV dilatation in patients in the mild FTR group. There were statistically significant differences between the three groups for the following RAS parameters: RASr, RAScd, RASct, RASr-c, and RASct-c (Table 4). As expected, RAS decreased with increasing TR severity in patients with FTR. Both inter- and intraobserver variabilities were very low in right heart volume and RAS parameters (Table 5).

Relationships of TR volume with right heart chamber remodeling

In patients with FTR, TR volume showed a strong positive correlation with RAVmin (r=0.864; P<0.001). Additionally, TR volume was moderately correlated with RVESV and RAEF (r=0.640; r=−0.712; both P<0.001) and weakly correlated with RVGS (r=0.344; P<0.001) and RVEF (r=−0.305; P=0.002) (Figure 4). The multiple stepwise linear regression analysis, which included RAVmin, RAEF, RVESV, RV EF, and RVGS, resulted in an R2 value of 0.672. This indicated that the model could explain 67% of the variability in TR volume. The results suggested that only RAVmin was an independent correlate of the increase in TR volume (β=0.820; P<0.001), with the unstandardized coefficient (B) of 0.675 for RAVmin. Therefore, for every 10 mL increase in RAVmin, TR volume increased by 6.8 mL.

Figure 4 Correlation analysis of RAVmin, RVESV, RAEF, RVGS, and RVEF with TR volume (n=100). TR, tricuspid regurgitation; RAVmin, right atrium minimum volume; RVESV, right ventricular end-systolic volume; RAEF, right atrial ejection fraction; RVGS, right ventricular globe strain; RVEF, right ventricular ejection fraction.

Right atrial strain (RAS) parameters in patients with different grades of FTR

Through univariate logistic regression, we found that RASr, RAScd, RASct, RASr-c, and RASct-c were all correlated with FTR severity. Moreover, from the receiver operating characteristic curves for the regression prediction probabilities of the above strain parameters, we found that RASr, and RAScd had a strong predictive performance for moderate-to-severe FTR (area under the curve >0.800; Table 6, Figure 5).

Figure 5 ROC curves for predicting moderate-to-severe FTR. AUC, area under the curve; RASr, right atrial reservoir strain; RAScd, right atrial conduit strain; RASct, right atrial contraction strain; RASr-c, right atrial reservoir circumferential strain; RASct-c, right atrial contraction circumferential strain; ROC, receiver operating characteristic; FTR, functional tricuspid regurgitation.

A multivariate logistic regression model was developed to assess the predictors of FTR severity and included RAS parameters. The results indicated that RASr [odds ratio (OR) =0.702; 95% confidence interval (CI): 0.575–0.857; P=0.001], RAScd (OR =1.308; 95% CI: 1.098–1.558; P=0.003), and RASr-c (OR =0.823; 95% CI: 0.684–0.990; P=0.04) were predictor variables associated with increased TR severity in patients with FTR (Table 6, Figure 6).

Figure 6 Logistic regression forest map of RAS in patients with FTR. OR, odds ratio; CI, confidence interval; RASr, right atrial reservoir strain; RAScd, right atrial conduit strain; RASct, right atrial contraction strain; RASr-c, right atrial reservoir circumferential strain; RASct-c, right atrial contraction circumferential strain; FTR, functional tricuspid regurgitation; RAS, right atrial strain.

Discussion

There were three principal findings in this study: (I) patients with moderate-to-severe FTR exhibited advanced RA remodeling, and RA remodeling seemed to be more sensitive to the pathophysiological process of right heart remodeling in FTR; (II) RAVmin is a major determinant of increased TR volume in patients with FTR; and (III) the RAS parameters of the RASr, RAScd, and RASr-c were predictor variables associated with increased TR severity in patients with FTR.

The remodeling of the RA has received increased attention in the last few years due to its important role in the pathophysiology of TR. Two studies (17,18) based on cardiac computed tomography angiography by Nemoto et al. have consecutively reported that increased RA volume is an early and sensitive indicator of mild TR, whereas RV dilatation and functional decline are late events in moderate and more severe TR. In the study by Guta et al. (19), 93% of patients with FTR showed RA dilatation. RA remodeling was also explored in Harada et al.’s study (20), in which 78% of patients showed RA dilatation. In the study by Galloo et al. (3), which included 586 patients with severe FTR, the patients exhibited mild RV dilatation (end-diastolic area of 13.8±6.5 cm²/m²) and moderately severe RA dilatation (maximal area 15.0±5.3 cm²/m²). This suggests that RA enlargement is more prevalent than is RV dilatation and/or dysfunction. Referring to previous studies (19,21), we used 4D automated quantitative echocardiography to quantify the volume and function of the right heart, and the results of the study similarly confirmed the role of RAVmin as a major determinant of TR volume in patients with FTR.

There are three phases of normal RA activity: reservoir, (passive) conduit, and (active) contractile (22). After ventricular end-diastole, the RA fills and stretches, and its strain curve increases, reaching its peak in the ventricular end-systolic phase; this phase is the reservoir period of the RA (RASr and RASr-c and longitudinal and circumferential RAS). After ventricular end-systolic phase (ES), the RA rapidly deflates until its pressure is equal to that of the RV; this phase is the conduit period of the RA (RAScd and RAScd-c). The RA subsequently contracts, further ejecting blood into the RV, and the stress continues to decrease; this phase is the RA contraction period (RASct and RASct-c).

A recent systematic review (23) analyzed RAS parameters on 2D-STE and provided a range of normal reference values, reporting an average RASr of 44% (95% CI: 25% to 63%). This range was higher than that in our control group; meanwhile, another study (5) measured left atrial strain using the 4D Auto LAQ, and the LAsr range was similar to that in our control group. It is possible that the discrepancies between these studies could be due to different vendor measurement methods. Several other studies have also measured and reported RASr on 2D-STE. Galloo et al. (3) reported that reduced RASr is associated with all-cause mortality in patients with severe FTR. In another study (24), Kaplan-Meier curve analysis indicated that patients with an RASr of <9.4% were associated with a 3.2-fold increased risk of heart failure or cardiovascular death. Our study showed statistically significant differences in RASr, RAScd, RASct, RASr-c, and RASct-c between the three groups, which decreased with increasing TR severity. RASr, RAScd, and RASr-c were predictor variables associated with increased TR severity in patients with FTR. According to a recent report based on cardiac magnetic resonance (25), RAScd is an independent predictor of poor outcomes in patients with dilated cardiomyopathy. Wessels et al. (26) demonstrated through tissue biopsy that patients with end-stage pulmonary arterial hypertension exhibit a significant reduction in capillary density and interstitial and perivascular fibrosis in their RA tissues. In our study, we observed a significant decrease in right atrial function. Patients with severe FTR exhibited a decrease in RASr and RAScd, as well as an increase in stiffness. These findings support the hypothesis that patients with severe FTR have a similar outcome of RA remodeling.

The 4D automated quantitative echocardiography used in this study was able to dynamically measure structural and functional changes in the right heart. The current study indicates that remodeling of the RA occurs before remodeling of the RV in patients with severe FTR. Additionally, lower RASr and RAScd are independently associated with worse TR. Therefore, when evaluating patients with FTR, it is important to comprehensively assess the RA in addition to TR severity, etiology, and RV remodeling to optimize risk stratification. A series of RA parameters are intimately correlated with the severity of FTR. These discoveries not only deepen our understanding of the pathophysiological processes underlying FTR but also offer biomarkers for assessing the severity of the condition. In terms of patient management, these parameters empower physicians in identifying RA remodeling at an earlier stage, thereby facilitating the development of individualized treatment plans. Furthermore, they enhance the accuracy of prognostic assessments, enabling doctors to more precisely gauge patient risks and optimize long-term treatment protocols and follow-up strategies. Ultimately, these research findings hold the promise of driving the development of novel therapeutic approaches that can offer better management for patients with FTR.

Study limitations

Firstly, it is worth noting that as we employed a single-center design, some of our findings may be attributable to chance alone, necessitating confirmation in a larger, prospective study with a larger sample. Second, given the limited sample size, we were unable to categorize the patients with FTR based on their specific etiology, nor could we draw comparisons between those with moderate FTR and those with severe FTR, potentially introducing bias into our results. Third, the 4D automated quantitative echocardiography technique employed in this study is still a relatively novel approach, with limited reporting in China and internationally. Our findings require further validation through large-scale datasets and comparisons with the more definitive cardiac magnetic resonance (gold standard) quantification methods. Finally, it is crucial to recognize that strain parameters vary between different vendors, rendering direct comparisons infeasible.

Conclusions

This study successfully achieved dynamic assessment of right heart volume and function with 4D automated quantitative echocardiography. During the progression of FTR disease, RA remodeling precedes RV remodeling, indicating that RA remodeling is more sensitive to the pathophysiological process of right heart remodeling in FTR. Notably, RAVmin was identified as the primary determinant of increased TR volume in patients with FTR. Furthermore, the OR values of the RA parameters, including RASr, RAScd, and RASr-c, were closely associated with increased severity of TR in patients with FTR.

Acknowledgments

Funding: This study was funded by the Key Program of Guangxi Natural Science Foundation (grant No. 2022JJD140147), the National Clinical Key Specialty Construction Project of China (Department of Cardiovascular Surgery, The First Affiliated Hospital of Guangxi Medical University), and the Clinical Key Specialty Construction Project of Guangxi (Department of Cardiothoracic Surgery, The First Affiliated Hospital of Guangxi Medical University).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-676/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-676/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by the Medical Ethics Committee of the First Affiliated Hospital of Guangxi Medical University (No. 2021-E477-01). Written informed consent was obtained from all participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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