Characteristics and prognostic significance of right atrium remodeling and tricuspid regurgitation after balloon pulmonary angioplasty—application value of echocardiography

Abstract

Objectives

Pulmonary hypertension-induced right ventricular (RV) overload can result in right atrial (RA) remodeling and tricuspid regurgitation (TR), which in turn affects RV function and negatively impacts patient prognosis. This study aimed to clarify the prognostic significance of RA function and TR in patients with chronic thromboembolic pulmonary hypertension (CTEPH).

Methods

For this retrospective analysis of 97 patients with CTEPH who underwent balloon pulmonary angioplasty (BPA), clinical, hemodynamic, and echocardiographic data were acquired before the first BPA and after the final BPA. The composite end point was hospitalization due to right heart failure and all-cause death.

Results

After BPA, patients experienced significant increases in RA reservoir strain (RASr, 26.7 ± 9.1% vs. 35.2 ± 11.3%, P<.001) and conduit strain (15.0[9.6] % vs. 22.6[9.6] %, P<.001), with no significant change in RA contraction strain. TR was significantly improved after BPA, decreasing from 49.5% to 22.7% in patients with significant TR (P<.001). Over a mean follow-up of 24.7 ± 12.4 months, 22 patients met the composite end point. On multivariate Cox regression analysis, Right atrial reservoir strain (RASr) was independently associated with composite clinical outcomes(P=.012). Patients with post-BPA RASr ≥ 29.85% exhibited superior event-free survival compared to those with lower values.

Conclusion

Right atrial reservoir and conduit functions were impaired in CTEPH patients and showed significant improvement following BPA. Post-BPA RASr ≥ 29.85% demonstrated an independent association with long-term clinical outcomes. These findings support the inclusion of RA strain in postoperative assessments and long-term follow-up of CTEPH patients treated with BPA.

Clinical relevance statement

In this study, 2D-speckle tracking echocardiography can be used to better monitor right heart status of patients. To some extent, it can help clinicians to provide better treatment for patients and improve the quality of life of patients.

Key points

∙ Balloon pulmonary angioplasty (BPA) improved right atrial function in CTEPH patients, mainly reservoir and conduit function.

∙ The postoperative RASr ≥ 29.85% demonstrated an independent association with long-term clinical outcomes.

∙ These findings support the inclusion of RA strain in postoperative assessments and long-term follow-up of CTEPH patients treated with BPA.

Introduction

In chronic thromboembolic pulmonary hypertension (CTEPH), long-term afterload induces right ventricular (RV) deformation and dysfunction, which subsequently results in changes in right atrial (RA) size and function as well as tricuspid regurgitation (TR) [1, 2]. Conversely, the condition of the RA indirectly reflects RV overload and failure, which are associated with an adverse prognosis [3, 4]. Thus, the RA–RV axis is crucial in the pathophysiology of pulmonary hypertension [5]. TR also is a common comorbidity of pulmonary hypertension (PH) [6]. Secondary TR in patients with CTEPH involves deformation of the tricuspid valve apparatus caused by RV remodeling and dilation and is associated with worsening symptoms and decreased functional status [7].

In previous studies, two-dimensional speckle tracking echocardiography (2D-STE) has been applied as a feasible and reproducible method for evaluating RA function, providing new insights into the understanding of cardiopulmonary disease [8, 9]. The three main components of RA function are reservoir, conduit, and contraction [10]. Currently, transthoracic echocardiography (TTE) is the preferred technique for assessing TR and can provide information for assessing its etiology, severity, and impact [11].

At present, balloon pulmonary angioplasty (BPA) is recommended as a first-line treatment for inoperable cases of CTEPH [1]. Many studies have demonstrated that BPA results in improved RV function, but research on the effects of BPA on RA function and TR remains limited. Therefore, the purpose of this study was to investigate the characteristics and prognostic significance of RA function and TR in BPA-treated CTEPH patients using multimodal echocardiography.

Methods

Study population

Based on sufficient image quality and data available, a total of 106 CTEPH patients who underwent BPA surgery between January 2017 and October 2023 were screened for inclusion in this single-center retrospective study. After 9 of these patients were excluded due to missing follow-up data, 97 patients were ultimately included. Patients undergoing TV surgery who had existing primary significant TR were not included. TR was secondary to CTEPH in all enrolled patients. Control group data came from a previous study using the same vendor [12, 13].

Clinical and hemodynamic data were acquired from the electronic medical records system. Echocardiographic data were collected before the first BPA and within 3–6 months after the final BPA. Follow-up was performed routinely by querying electronic medical records, telephone communication, or requesting information from the patient’s physician. Patients were analyzed from inclusion until reaching the end point or the last follow-up. The follow-up period was defined from the final BPA session until the occurrence of end point events or until the censored date. The composite end point was defined as hospitalization for right heart failure and all-cause death. Hospitalization for right heart failure was determined by respiratory specialists based on the appearance of typical symptoms and signs, such as dyspnea, edema of the lower extremities, or distention of the jugular vein.

All CTEPH diagnoses were made by two physicians experienced in treating PH and in accordance with 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines for PH [1].

Echocardiography

All patients underwent a comprehensive TTE examination using an EPIQ7C, equipped with an X5-1 phased array probe (Philips Healthcare, MA, USA). All measurements and evaluations were performed according to the American Society of Echocardiography (ASE) guidelines [14]. Pulmonary artery systolic pressure (PASP) was determined from the TR pressure and right atrial pressure (RAP). RAP was obtained based on the internal diameter of the inferior vena cava and the respiratory collapse rate. TR was evaluated using a comprehensive assessment approach including two-dimensional and Doppler echocardiography (Fig. 1). The degree of TR was classified as mild, moderate, or severe based on the comprehensive assessment of right heart structure, using qualitative, semi-quantitative, and quantitative measures. Moderate or greater regurgitation was graded as significant TR [11] and also considered residual TR after BPA. RV function was quantitatively assessed using the following parameters: tricuspid annular plane systolic excursion (TAPSE), peak systolic velocity of the tricuspid annulus (S’), right ventricular index of myocardial performance (RIMP), and RV fractional area change (FAC). Left ventricular (LV) function was represented by the LV ejection fraction (LVEF) determined by the simplified Simpson method. Data for the left ventricular eccentric index (LVEI), RV base diameter (RVD_basal), and tricuspid regurgitation peak velocity (TRV) also were collected.

Fig. 1.

Echocardiographic images from a representative patient

2D-STE

Images taken of the RV-focused apical four-chamber view with a frame rate of 60–80 frames/s recorded in DICOM format were analyzed. Strain parameters were measured offline using QLAB 13.0 (Philips, Andover, MA) by two experienced echocardiologists. These parameters included RA reservoir strain (RASr), conduit strain (RAScd), contraction strain (RASct), RV free wall longitudinal strain (RVFWLS) and RV global longitudinal strain (RVGLS). RA strain was analyzed using a left atrial (LA) strain software. Three points were sketched manually, including both sides of the tricuspid valve annulus and RA roof, and then the program automatically tracked the endocardial boundary [10]. If the result was not satisfactory, the boundary was adjusted manually (Fig. 1). Atrial strain curves were generated from the baseline zero set to the onset of ventricular systole (R-R gated method). RV strain was analyzed using a RV strain software. All strain data are expressed in absolute values.

Right heart catheterization and interventional procedures

Hemodynamic parameters were measured upon passage of a Swan–Ganz catheter through the internal jugular vein to the right cardiac system. These included central venous pressure (CVP), mean pulmonary artery pressure (mPAP), pulmonary vascular resistance (PVR), pulmonary capillary wedge pressure (PCWP), and cardiac index (CI). Hemodynamic parameters were evaluated at 3 to 6 months following the BPA procedure.

Patients with CTEPH who were not candidates for surgery or who were unwilling to undergo PEA were considered BPA candidates. Patients’ eligibility and suitability for treatment with BPA were assessed jointly by two physicians experienced in treating PH and a BPA interventionist. Each patient received at least three BPA sessions. During the study period, waiting times for BPA were extended due to the coronavirus disease 2019 (COVID-19) pandemic, but the temporal gap between two successive BPA sessions did not exceed 12 months at most. Drawing on the established criteria [15], immediate success following BPA was defined as the achievement of pulmonary flow grade (PFG) 3 or 2 post-dilation, representing a significant improvement in PFG, with PFG 2 considered an acceptable success for complex lesions.

Statistical analysis

Data for continuous variables are expressed as mean ± standard deviation (SD) or median (interquartile range), and those for categorical variables are expressed as frequency (percentage). A paired t test or Wilcoxon signed-rank test was used to compare data from the same patient before and after BPA procedures, as appropriate. Patients were categorized into two groups according to the degree of residual tricuspid regurgitation and achievement of target hemodynamic goals following BPA. The differences between groups were compared using the Student t-test or Mann–Whitney U test for continuous variables or the chi-square test for categorical variables. Univariable and multivariable logistic regression analyses were performed to identify the variables independently associated with the minimum hemodynamic goal of BPA (mPAP < 30 mmHg) [16]. Receiver operating characteristic (ROC) analysis was performed within the study cohort to calculate optimal prognostic cutoff values using the maximum Youden index method. The Kaplan–Meier method and log-rank test were applied for analysis of event-free survival during the follow-up period. We performed univariable and multivariable Cox proportional hazards analyses to identify the independent factors associated with the composite end point. The LA strain data for 15 patients were randomly selected for analysis of inter-observer variability, which was assessed by calculating the intraclass correlation coefficient (ICC). The ICC values for LASr, LAScd, LASct were 0.91,0.79, and 0.81, respectively, indicating a high level of agreement (all ICCs > 0.7).

Two-sided P values < 0.05 were considered indicative of statistical significance. All data were analyzed using SPSS version 25 (SPSS Inc., Chicago, IL, USA) and GraphPad Prism 8 (GraphPad, La Jolla, CA).

Results

Basic and clinical characteristics of patients before and after BPA

A total of 97 CTEPH patients treated with BPA were included in the study. The median age of patients was 60 (16) years, and 62.9% of them were female. The characteristics of patients preoperatively and postoperatively are presented in Table 1.

Table 1.

Clinical characteristics of CTEPH patients before and after treatment with BPA

Variables	Before	After	P
Demographics
Age, years	60（16）
Female (%)	61（62.9）
BSA, cm2	1.7（0.2）
Echocardiography
PASP, mmHg	89.1（27.2）	56.4（33.0）	＜.001
LVEI	1.3（0.2）	1.1（0.2）	＜.001
RVDbasal,mm	45.8±7.2	38.0（9.0）	＜.001
TRsignificant，n(%)	48（49.5）	22（22.7）	＜.001
TRV, cm/s	438.0（77.0）	347.0（100.0）	＜.001
TAPSE, mm	14.6±3.2	17.6±3.5	＜.001
S', cm/s	9.0（3.0）	10.5（2.9）	＜.001
RIMP	0.8（0.3）	0.6（0.2）	＜.001
RVFAC, %	29.8±11.4	39.1±10.5	＜.001
LVEF, %	65.0±5.3	65.4±4.7	0.55
2D-STE
RASr, %	26.7±9.1	35.2±11.3	＜.001
RAScd, %	15.0（9.6）	22.6（9.6）	＜.001
RASct, %	14.6±5.3	15.3±6.2	0.15
RVFWLS, %	16.1（7.1）	20.1（11.5）	＜.001
RVGLS, %	13.2（7.0）	17.4（7.8）	＜.001
Hemodynamics
CVP, mmHgmPAP，mmHg	8.0（6.0）51.0±11.1	6.5（5.0）35.5±11.5	0.001＜.001
PVR，WU	10.2（6.1）	5.3（5.0）	＜.001
PCWP，mmHg	10.0±4.6	9.5±3.6	0.50
CI，L/min/m2	2.2（0.8）	2.4（0.6）	0.08
Clinical indication
WHO FC
I/II/III/IV	7/44/38/8	22/55/16/4	＜.001
6WMD，m	387.0（127.5）	464.0（88.3）	＜.001
NT-proBNP, ng/L	672.5（1743.5）	127.5（285.0）	＜.001

Abbreviations BSA body surface area, PASP pulmonary artery systolic pressure by echocardiography, LVEI left ventricular eccentric index, RVD_basal right ventricular base diameter, TR_significan significant tricuspid regurgitation, TRV tricuspid regurgitation peak velocity, TAPSE tricuspid annular plane systolic excursion, S' peak systolic velocity of the tricuspid annulus, RIMP right ventricular index of myocardial performance, RVFAC right ventricular fractional area change, LVEF left ventricular ejection fraction, RASr right atrial reservoir strain, RAScd right atrial conduit strain, RASct right atrial contraction strain, RVFWLS right ventricular free wall longitudinal strain, RVGLS right ventricular global longitudinal strain, CVP central venous pressure, mPAP mean pulmonary artery pressure, PVR pulmonary vascular resistance, PCWP pulmonary capillary wedge pressure, CI cardiac index, WHO FC World Health Organization Functional Class, 6MWD 6-minute walking distance, NT-proBNP N-terminal pro-brain natriuretic peptide, BPA balloon pulmonary angioplasty

After BPA, significant reductions were observed in the mPAP (from 51.0 ± 11.1 mmHg to 35.5 ± 11.5 mmHg, P<.001), PVR (from 10.2 [6.1] WU to 5.3 [5.0] WU, P < .001), CVP (from 8.0 [6.0] mmHg to 6.5 [5.0] mmHg, P<.001), and CI (from 2.2 [0.8] L/min/m² to 2.4 [0.6] L/min/m², P=.008), while no significant change in PCWP occurred. BPA also resulted in a significant reduction in the proportion of patients with World Health Organization Functional Class (WHO FC) III/IV (from 47.4% to 20.6%). With respect to ultrasonic parameters, BPA resulted in a significant decrease in PASP (from 89.1 [27.2] mmHg to 56.4 [33.0] mmHg, P<.001), LVEI (from 1.3 [0.2] to 1.1 [0.2], P<.001), TRV (from 438.0 [77.0] cm/s to 347.0 [100.0] cm/s, P<.001) and RIMP (from 0.8 [0.3] to 0.6 [0.2], P<.001). BPA also resulted in significant improvements in TAPSE (from 14.6 ± 3.2 mm to 17.6 ± 3.5 mm, P<.001), S’ (from 9.0 [3.0] cm/s to 10.5 [2.9] cm/s, P<.001), and FAC (from 29.8 ± 11.4% to 39.1 ± 10.5%, P<.001), while no significant change in LVEF was observed. 2D-STE imaging showed significant increases in two components of RA phasic strain, including RASr (from 26.7%±9.1% to 35.2%±11.3%, P<.001) and RAScd (from 15.0% [9.6%] to 22.6% [9.6%], P<.001) but not in RASct. Compared with levels in the control group, RASr (controls: 35.92%±6.38% vs. before BPA 26.7%±9.1%) and RAScd (controls: 24.21%±7.15% vs. before BPA 15.0% [9.6%]) appeared to be reduced. Meanwhile, RVFWLS (from 16.1% [7.1%] to 20.1% [11.5%], P<.001) and RVGLS (from13.2% [7.0%] to 17.4% [7.8%], P<.001) also improved significantly.

Table 2 presents the utilization of PH-specific medical therapies before and after BPA. Following the procedure, riociguat was used in 28.9% of patients, representing a notable presence among targeted therapies. In contrast, the use of endothelin receptor antagonists (ERA), phosphodiesterase-5 inhibitors (PDE-5 inhibitors), and prostacyclin analogues after BPA was 9.3%, 2.1%, and 1.0%, respectively. Regarding anticoagulation, warfarin was prescribed in 50.5% and rivaroxaban in 46.4% of patients after BPA, reflecting the distribution of antithrombotic management in the post-procedure period.

Table 2.

The proportion of patients receiving PH-specific medical therapy

PH medical therapy	Before BPA	After BPA
PH targeted therapy
Riociguat	10 (10.3)	28(28.9)
ERA	15(15.5)	9(9.3)
PDE 5 inhibitors	19(19.6)	2(2.1)
Prostacyclin analogues	6(6.2)	1(1.0)
Anticoagulation
Warfarin	74(76.3)	49(50.5)
Rivaroxaban	36(37.1)	45(46.4)

Values are expressed as frequency (percentage)

Abbreviations PH pulmonary hypertension, ERA endothelin receptor antagonists, PDE-5 inhibitors phosphodiesterase-5 inhibitors

In this cohort, BPA lesions were predominantly distributed bilaterally across the pulmonary arteries, primarily involving the segmental and subsegmental vessels, with a predilection for the bilateral lower lobe segmental arteries and their branches. The lesion morphologies included web lesions, ring-like stenosis, subtotal occlusion, total occlusion, and tortuous lesions. A median of 5 sessions were performed, with a median procedure duration of 334 days. A total of 28.6 ± 11.7 vessels were treated, averaging 5.5 ± 1.4 vessels per session. Regarding lesion morphology, web lesions were the most common, whereas total occlusion and tortuous lesions were rarely observed.(Table 3).

Table 3.

The information on the procedural dose of BPA

BPA procedures
Number of BPA sessions	5 (2)
Duration of BPA	334 (432)
The total number of treated vessels	28.6±11.7
The median number of treated vessels per session	5.5±1.4
Web	17 (10)
Ring-like stenosis	5 (6)
Subtotal occlusion	2 (3)
Total occlusion	0 (2)
Tortuous lesions	0 (0)

Abbreviations BPA balloon pulmonary angioplasty

Data are presented as median  (interquartile range [IQR])

Post-BPA and follow-up outcomes

Fifty patients (50/97, 51.5%) achieved the minimum hemodynamic goal of BPA (mPAP < 30 mmHg). Table 4 compares echocardiographic parameters and clinical characteristics between patients with post-BPA mPAP < 30 mmHg and those with mPAP ≥ 30 mmHg. Patients with mPAP < 30 mmHg demonstrated significantly better RV function, with higher RVFWLS (23.9 ± 5.5% vs. 17.0 ± 5.4%) and RVGLS (19.6 ± 4.0% vs. 14.2 ± 4.9%; both P< .001). RA strain parameters (RASr, RAScd, and RASct) were also significantly higher in this group (all P≤.001). Clinically, NT-proBNP levels were markedly lower in the mPAP < 30 mmHg group (69.0 vs. 223.0 ng/L, P<.001), whereas WHO FC and 6MWD showed no significant differences between the two groups.

Table 4.

Comparison of characteristics between patients with post-BPA mPAP < 30 mmHg and those with mPAP ≥ 30 mmHg

Variables	mPAP ≥30mmHg	mPAP <30mmHg	P
Echocardiography
PASP, mmHg	71.7（36.3）	45.0（15.5）	＜.001
LVEI	1.2（0.3）	1.1（0.1）	＜.001
RVDbasal,mm	42.0（9.3）	35.0（5.5）	＜.001
TRV, cm/s	403.2±73.1	317.9±43.8	＜.001
TAPSE, mm	16.4±3.7	18.7±2.7	＜.001
S', cm/s	10.0（3.3）	11.3（3.4）	0.153
RIMP	0.63（0.3）	0.54（0.2）	0.001
RVFAC, %LVEF, %	34.2±9.565.6±5.2	44.5±8.565.2±4.2	<.0010.761
2D-STE
RASr, %	28.9±11.3	40.6±8.2	＜.001
RAScd, %	16.4±9.2	23.2±6.4	0.001
RASct, %	12.5±5.6	17.4±5.4	0.001
RVFWLS, %	17.0±5.4	23.9±5.5	＜.001
RVGLS, %	14.2±4.9	19.6±4.0	＜0.001
Clinical indication
WHO FC
I/II/III/IV	10/25/10/2	12/30/6/2	0.270
6WMD，m	430.0（98.0）	465.0（92.5）	0.099
NT-proBNP, ng/L	223.0（510.0）	69.0（134.0）	<0.001

Abbreviations PASP pulmonary artery systolic pressure by echocardiography, LVEI left ventricular eccentric index, RVD_basal right ventricular base diameter, TR_significansignificant tricuspid regurgitation, TRV tricuspid regurgitation peak velocity, TAPSE tricuspid annular plane systolic excursion, S'peak systolic velocity of the tricuspid annulus, RIMP right ventricular index of myocardial performance, RVFAC right ventricular fractional area change, LVEF left ventricular ejection fraction, RASr right atrial reservoir strain, RAScd right atrial conduit strain, RASct right atrial contraction strain, RVFWLS right ventricular free wall longitudinal strain, RVGLS right ventricular global longitudinal strain, WHO FC World Health Organization Functional Class, 6MWD 6-minute walking distance, NT-proBNP N-terminal pro-brain natriuretic peptide, BPA balloon pulmonary angioplasty

On univariable logistic regression analysis, PASP, TAPSE, LVEI, severity of TR, TRV, FAC, RASr, RVFWLS and RVGLS were all associated with achievement of mPAP < 30 mmHg. Due to multicollinearity among these echocardiographic parameters (particularly between RVFWLS and RVGLS, as well as among RV functional indices), and considering the established clinical relevance of PASP, the final multivariable logistic regression analysis included RASr, RVFWLS, and PASP. Multivariable analysis demonstrated that RVFWLS (OR: 1.48, 95%CI 1.13–1.94, P=.004) and PASP (Odds ratio [OR]: 0.95, 95%CI 0.91-1.0, P=.033) were independently associated with reaching the hemodynamic goal, whereas RASr was not independently predictive(OR: 1.03, 95%CI 0.95–1.13, P=.467; Table 5 ).

Table 5.

Univariable and multivariable logistic regression analyses of predictors of post-BPA achievement of mPAP < 30 mmHg

Variable	Univariable analysis			Multivariable analysis
	OR	95%CI	P value	OR	95%CI	P value
Age, years	1.03	0.99–1.07	0.07
Female (%)	0.76	0.33–1.73	0.51
BSA, cm2	0.30	0.03–3.09	0.31
PASP, mmHg	0.96	0.93–0.98	< 0.001	0.95	0.91-1.0	0.033
LVEI	0.02	0.01–0.30	0.004
TRsignificant, n(%)	0.18	0.08–0.43	< 0.001
TRV, cm/s	0.99	0.98–0.99	0.001
TAPSE, mm	1.23	1.07–1.43	0.005
S’,cm/s	1.00	0.82–1.21	0.96
RIMP	0.28	0.04–1.75	0.17
RVFAC,%	1.08	1.02–1.13	0.003
LVEF,%	1.02	0.956–1.098	0.50
RASr	1.14	1.05–1.23	0.001	1.03	0.95–1.13	0.467
RVFWLS	1.22	1.08–1.38	0.001	1.48	1.13–1.94	0.004
RVGLS	1.24	1.09–1.41	0.001

Abbreviations BSA body surface area, PASP pulmonary artery systolic pressure by echocardiography, LVEI left ventricular eccentric index, RVD_basal right ventricular base diameter, TR_significan significant tricuspid regurgitation, TRV tricuspid regurgitation peak velocity, TAPSE tricuspid annular plane systolic excursion, S’ peak systolic velocity of the tricuspid annulus, RIMP right ventricular index of myocardial performance, RVFAC right ventricular fractional area change, LVEF left ventricle ejection fraction, RASr right atrial reservoir strain, RVFWLS right ventricular free wall longitudinal strain, RVGLS right ventricular global longitudinal strain

After BPA, the proportion of patients with significant TR significantly decreased (from 49.5% to 22.7%, P<.001), with 22 patients having residual TR after BPA. The patients were then divided into residual TR and non-residual TR groups. On TTE, patients with residual TR had worse PASP, LVEI, RVD_basal TRV, TAPSE, RIMP, and FAC, whereas S’ and LVEF did not differ between the two groups. Significant differences were observed in RA function between the two groups, with patients who did not have residual TR showing greater RASr, RAScd, and RASct values. Patients without residual TR also exhibited better heart function, but exercise capacity was comparable between the two groups (Table 6). Kaplan–Meier analysis also indicated that postoperative residual TR was associated with composite endpoint events (log-rank test P<.001; Fig. 3).

Table 6.

Clinical characteristics of CTEPH patients with and without residual tricuspid regurgitation after BPA

Variables	non-residual TR	residual TR	P
Echocardiography
PASP, mmHg	50.9±14.1	95.8±18.7	0.001
LVEI	1.1(0.2)	1.3±0.2	0.001
RVDbasal,mm	36.9±4.7	45.0(10.0)	0.001
TRV, cm/s	328.5±48.8	458.5±52.9	0.001
TAPSE, mm	18.5±2.9	14.5±3.6	0.001
S', cm/s	11.0(3.5)	9.8(3.8)	0.211
RIMP	0.6(0.2)	0.7±0.3	0.022
RVFAC, %	42.5±9.0	30.0±8.6	0.001
LVEF, %	65.2±4.4	66.0±5.6	0.47
2D-STE
RASr, %	38.5±8.9	23.8±12.8	0.001
RAScd, %	21.9±6.8	11.7±9.5	0.001
RASct, %	16.8±6.5	12.1±6.1	0.015
RVFWLS, %	21.7±6.2	14.7±5.6	0.001
RVGLS, %	18.1±4.6	12.1±4.7	0.001
Hemodynamics
CVP, mmHg	5.8±2.9	9.9±4.2	0.001
mPAP, mmHg	31.0(11.0)	44.0(19.3)	0.001
PVR, WU	377.0(236.0)	807.5(435.0)	0.001
PCWP, mmHg	9.3±3.1	10.0(6.5)	0.803
CI, L/min/m2	2.6±0.6	2.2±0.6	0.02
Clinical indication
WHO FC
I/II/III/IV	18/44/11/2	4/11/5/2	0.027
6WMD, m	451.8±79.0	410.0±92.8	0.079
NT-proBNP, ng/L	76.0(160.0)	521.5(2209.0)	0.001

Abbreviations PASP pulmonary artery systolic pressure by echocardiography, LVEI left ventricular eccentric index, RVD_basal right ventricular base diameter, TRV tricuspid regurgitation peak velocity, TAPSE tricuspid annular plane systolic excursion, S' peak systolic velocity of the tricuspid annulus, RIMP right ventricular index of myocardial performance, RVFAC right ventricular fractional area change, LVEF left ventricle ejection fraction, RASr right atrial reservoir strain, RAScd right atrial conduit strain, RASct right atrial contraction strain, RVFWLS right ventricular free wall longitudinal strain, RVGLS right ventricular global longitudinal strain, CVP central venous pressure, mPAP mean pulmonary artery pressure, PVR pulmonary vascular resistance, PCWP pulmonary capillary wedge pressure, CI cardiac index, WHO FC World Health Organization Functional Class, 6MWD 6-minute walking distance, NT-proBNP N-terminal pro-brain natriuretic peptide, BPA balloon pulmonary angioplasty

Fig. 3.

Kaplan–Meier survival curves for the effects of TR and RA function on CTEPH patient survival post-BPA

Over a mean follow-up of 24.7 ± 12.4 months, 22 (22.7%) patients experienced composite endpoint events. Four patients died, with two deaths attributed to right heart failure due to PH and two to unknown causes. Univariable Cox regression analysis found that PASP, TAPSE, LVEI, severity of TR, TRV, FAC, RASr, RVFWLS and RVGLS were all associated with composite end points. As described above, the final multivariable Cox model included RASr, RVFWLS, and PASP. After adjustment, both RASr (Hazard ratio [HR]: 0.91, 95%CI 0.84–0.98, P=.012) and RVFWLS (HR: 0.87, 95%CI 0.76–0.98, P=.028) remained independently associated with composite endpoints, whereas PASP lost statistical significance ( P=.959, Table 7). ROC curve analysis was performed to evaluate the prognostic discriminative ability of post‑BPA RASr in this cohort. The optimal cutoff value was determined as 29.85% using the maximum Youden index, which yielded a sensitivity of 92.5%, a specificity of 88.2%, and an AUC of 0.925 (95% CI: 0.828–1.000, Fig. 2), indicating excellent discrimination. Patients were subsequently stratified based on post‑BPA RASr ≥ 29.85% vs. <29.85%. Kaplan–Meier analysis revealed significantly worse event‑free survival in patients with RASr below the cutoff compared with those above it (log-rank test P<.001; Fig. 3).

Table 7.

Univariable and multivariable Cox regression analyses for determinants of composite end points

Variable	Univariable analysis			Multivariable analysis
	HR	95%CI	P value	HR	95%CI	P value
Age, years	1.03	0.99–1.07	0.17
Female (%)	1.60	0.69–3.71	0.28
BSA, cm2	0.78	0.04–14.99	0.87
PASP, mmHg	1.03	1.02–1.05	<0.001	1.0	0.97–1.03	0.959
LVEI	348.32	21.37-675.27	<0.001
TRsignificant, n(%)	10.12	3.64–28.12	<0.001
TRV, cm/s	1.01	1.01–1.02	<0.001
TAPSE, mm	0.73	0.64–0.83	<0.001
S’,cm/s	1.04	0.93–1.16	0.50
RIMP	4.45	1.02–19.39	0.05
RVFAC,%	0.90	0.85–0.95	<0.001
LVEF,%	1.04	0.94–1.15	0.43
RASr	0.90	0.86–0.95	<0.001	0.91	0.84–0.98	0.012
RVFWLS	0.83	0.76–0.90	<0.001	0.87	0.76–0.98	0.028
RVGLS	0.82	0.74–0.90	<0.001

Abbreviations BSA body surface area, PASP pulmonary artery systolic pressure by echocardiography, LVEI left ventricular eccentric index, RVD_basal right ventricular base diameter, TR_significan significant tricuspid regurgitation, TRV tricuspid regurgitation peak velocity, TAPSE tricuspid annular plane systolic excursion, S’ peak systolic velocity of the tricuspid annulus, RIMP right ventricular index of myocardial performance, RVFAC right ventricular fractional area change, LVEF left ventricle ejection fraction, RASr right atrial reservoir strain, RVFWLS right ventricular free wall longitudinal strain, RVGLS right ventricular global longitudinal strain

Fig. 2.

ROC curve of post BPA RASr for predicting composite endpoints

Discussion

The main findings of this retrospective study of CTEPH patients treated with BPA are: (1) RA function (both reservoir and conduit function) was impaired in patients with CTEPH, and both RA function and TR were significantly improved after BPA treatment; (2) significant residual TR was observed in 22 of 97 patients and was associated with worse cardiac morphology, function, and hemodynamics after BPA; and (3) A RASr cutoff of 29.85% was associated with better long-term prognosis.

The RA plays an important role in the development of PH, but quantitative evaluation of RA function is challenging [17]. RA strain provides one method for quantifying RA function [17], with three components that can be measured (RASr, RAScd, and RASct). In the present study, CTEPH patients showed significant improvement in RASr and RAScd after treatment with BPA, while no change in RASct was observed after treatment. A previous study that used cardiac magnetic resonance imaging (CMRI) to assess the effects of BPA on RA function produced similar results [18], and earlier research has shown consistent findings for other types of PH [3]. These findings in the present study indicate that late active systolic function was preserved in the included patients. Roca et al. demonstrated that impaired RA function is associated with RV dysfunction and overload, independent of hemodynamics [3]. Later, Tello et al. reported that the altered RA phase function is predominantly related to RV diastolic dysfunction [5]. Chronic PH leads to RV hypertrophy and stiffness, and in order to promote RV filling, the RA responds to increased RV pressure by deforming until excessive RA dilation occurs [5]. When the RA preload reserve reaches the limit, subsequent RA–RV uncoupling occurs [5, 19]. The RASr plays a key role in the progression of PH and is associated with clinical outcomes and mortality among patients [5, 20]. A previous prospective study established that RASr can independently predict all-cause death and heart failure in patients with severe TR, with a RASr cut-off value of < 9.4% predicting outcomes with good accuracy [21]. These previous findings led to greater awareness of the importance of the RA–RV axis in patients with PH. The results of the present study also demonstrate that RASr was independently associated with all-cause mortality and right heart failure hospitalization in CTEPH patients treated with BPA.

Multiple studies have reported that significant TR can lead to poor survival regardless of RV function and PH [2, 22, 23]. In a study on functional TR, Xavier et al. found that TR secondary to PH was associated with poor 1-, 5-, and 10-year survival rates [23]. A study reported in 2022 also found that residual TR after PEA could serve as a marker of worsened prognosis [2]. In the present study, residual TR was associated with the composite end point on the univariable regression analysis, but on the multivariable regression analysis, this association remained close but did not retain statistical significance (P = .067). Consistent with a previous study [2], we also observed that patients with residual TR showed worse right cardiac morphology, function, and hemodynamics after BPA than those without residual TR, while their left ventricular function did not differ from that of patients without residual TR. A study from the European Society of Cardiography (ESC) demonstrated that significant TR is strongly associated with all-cause mortality, and close echocardiographic surveillance is necessary for early and effective treatment [24]. Due to the small number of deaths in the present study, the relationship between significant TR and all-cause mortality was not analyzed, and this may also be an important reason for the difference in study results. On the other hand, tricuspid valve repair can improve symptoms and quality of life in patients with heart failure [25]. TR can reduce RV afterload to some extent, but it is unclear whether patients who have a much higher forward afterload will benefit [6]. Therefore, whether the presence of TR affects the prognosis of CTEPH patients treated with BPA requires further study.

Indeed, a total of 22 endpoint events occurred during the study period, of which 18 were re-admissions attributable to right heart failure. While we recognize that the ascertainment of these events may have been influenced by local practice patterns and subjective clinical judgment, the evaluation criteria remained consistent throughout the study. All events were adjudicated by senior respiratory specialists based on the presence of typical clinical manifestations, including dyspnea, lower extremity edema, or jugular venous distension. We further recognize that assessment of RA function at a single time point is insufficient for comprehensive prognostic evaluation. Over time, RA function, the severity of TR, and medical therapy regimens may evolve, and these dynamic factors could significantly influence patient prognosis. Among these, the impact of pharmacological therapy is likely the most substantial and complex to disentangle, as physicians may adjust medications during each clinical encounter based on the patient’s evolving condition. Such temporal variations in these parameters may limit the interpretation of RA strain as a stable prognostic marker in local diagnostic and treatment models.

Truong et al. [26] demonstrated the consistency of RA strain measured by cardiovascular magnetic resonance myocardial feature tracking (CMR-FT) and 2D-STE. Moreover, no significant difference was observed in strain values between the left and right atria in their study, supporting the use of the same measurement method. These findings indicate that measuring RA strain using left atrial (LA) software is feasible.

The present study is the first to evaluate the long-term prognosis of BPA-treated patients using STE, and the results revealed that RASr and residual TR were associated with patient outcomes. Given the small number of events and retrospective design of this study, our findings suggest an independent association between RA strain and long-term prognosis, rather than a definitive causal relationship. The 2022 ESC/ERS Guidelines for PH state that long-term follow-up is recommended after BPA treatment for patients with CTEPH [1]. Accordingly, these preliminary findings suggest that RA functional assessment may provide additional prognostic value and should be considered in future follow-up protocols, pending validation in larger prospective studies.

Limitations

This was a single-center, retrospective study, with a limited sample size. Due to the impact of COVID-19, many patients received BPA over a longer treatment course, but none of the intervals between two BPA sessions exceeded 1 year. Additionally, this study focused on the influence of RASr after BPA on the long-term outcomes of patients, and thus, this part was not analyzed in detail. The repeatability of RAScd and RASct measurements is not as good as that of RASr, and only the prognostic value of reservoir function was analyzed for reliability in this study. The control group data, derived from the same vendor as a prior study, are presented solely for contextual reference and warrant cautious interpretation. The complexity and heterogeneity of individual drug regimens render comprehensive analysis of medication effects particularly challenging and beyond the scope of this investigation, which constitutes an important limitation of this study. Finally, the number of deaths was small, and thus, predictors of all-cause death could not be analyzed separately.

Conclusion

RAS impairment was observed in patients with CTEPH and was improved significantly through treatment with BPA. Furthermore, RASr exhibited an independent association with endpoint events after adjusting for conventional echocardiographic measures. These results imply that incorporating RASr assessment into follow-up protocols might enhance risk stratification and support clinical decision-making in CTEPH management.

Abbreviations

2D

STE 2D-speckle tracking echocardiography

6MWD

6 min walking distance

ASE

American society of echocardiography

BPA

Balloon pulmonary angioplasty

BSA

Body surface area

CI

Cardiac index

CMR-FT

Cardiovascular magnetic resonance myocardial feature tracking

CTEPH

Chronic thromboembolic pulmonary hypertension

CVP

Central venous pressure

D_IVC

Diameter of inferior vena cava

ERS

European respiratory society

ESC

European society of cardiology

FAC

Right ventricular fractional area change

LA

Left atrial

LVEF

Left ventricle ejection fraction

LVEI

Left ventricular eccentric index

mPAP

mean Pulmonary artery pressure

NT-proBNP

N-terminal probrain natriuretic peptide

PASP

Pulmonary artery systolic pressure by echocardiography

PCWP

Pulmonary capillary wedge pressure

PEA

Pulmonary endarterectomy

PFG

Pulmonary flow grade

PH

Pulmonary hypertension

PVR

Pulmonary vascular resistance

RASr

Right atrial reservoir strain

RAScd

Right atrial conduit strain

RASct

Right atrial contraction strain

RHC

Right cardiac catheterization

RIMP

Right ventricular index of myocardial performance

ROC

Receiver operating characteristic

RV

Right ventricular

RVFWLS

RV free wall longitudinal strain

RVGLS

RV global longitudinal strain

RVEDA

RV end-diastolic area

RVESA

RV end-systolic area

S’

Peak systolic velocity of the tricuspid annulus

TAPSE

Tricuspid annular plane systolic excursion

TRV

Tricuspid regurgitation peak velocity

WHO FC

World health organization functional class

Authors’ contributions

Yaning Ma: Concept and design, Data acquisition and analysis, Investigation, and Initial writing; Dichen Guo: Data acquisition, Validation, Software. Jianfeng Wang: Resources, Visualization. Xinyuan Zhang, Huimin Hu and Yeqing Wang: Software, Data curation. Yuanhua Yang: Resources, Visualization. Xiuzhang Lv: Conceptualization, Supervision. Juanni Gong: Concept and design, Resources and Supervision. Yidan Li: Funding acquisition, Concept and design, Writing revision and Supervision.

Data availability

Data supporting the findings of this study may be obtained from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

The study protocol was approved by the Ethics Committee of Beijing Chaoyang Hospital. Informed consent was obtained from all patients. The study was conducted in accordance with the Declaration of Helsinki.

Consent for publication

Not Applicable.

Competing interests

The authors declare no competing interests.