1. Introduction
Pulmonary arterial hypertension (PAH) is a rare disease characterized by the chronic remodeling of distal pulmonary arteries, leading to a progressive increase in pulmonary arterial load [
1]. Despite recent advances in medical therapy and the development of novel strategies for combination therapy, PAH remains a severe clinical condition with a poor prognosis [
2]. During the 6th World Symposium on Pulmonary Hypertension (WSPH), the risk stratification of PAH patients was greatly emphasized, not only to define long-term prognosis but also to guide therapeutic management [
3]. Several multiparametric risk stratification approaches have been used to stratify PAH patients into low-, intermediate-, and high-risk based on expected transplant-free survival, with the aim of titrating medical therapy to achieve low-risk status [
4,
5,
6,
7,
8,
9]. However, studies have shown that the majority of PAH patients remained in the intermediate-risk category after receiving initial PAH-specific therapy [
5,
6,
7], including those receiving recommended upfront combination therapy with a phosphodiesterase type 5 inhibitor (PDE5-I) and an endothelin receptor antagonist (ERA) [
10,
11]. Several treatment options are available for patients who remain in the intermediate-risk category at follow-up [
4], and the best treatment strategy for these patients remains uncertain.
The role of 2D echocardiography, a routinely used imaging modality in PAH patients, has been underscored in risk assessment and stratification [
3,
12]. While both cardiac magnetic resonance and transthoracic echocardiography are non-invasive modalities instrumental for the evaluation of right ventricular (RV) morphology and function with relevant prognostic implications in PAH [
13,
14,
15,
16,
17], the role of imaging in risk stratification approaches has been limited to the assessment of right atrial (RA) area and the presence of pericardial effusion [
4,
7].
Given the prognostic value of RV echocardiographic parameters in predicting mortality risk in PAH and the need for a better risk stratification strategy, we hypothesized that echocardiography could be used to further stratify prevalent patients conventionally classified as intermediate-risk into intermediate-low- and intermediate-high-risk groups and thereby potentially help inform treatment decisions. Therefore, the aims of this study were to: (1) compare echocardiographic parameters between PAH risk groups, (2) evaluate the prognostic value of these parameters in predicting mortality, and (3) incorporate identified parameters in the risk stratification of PAH patients.
4. Discussion
In this study, echocardiography was used to refine an existing PAH risk stratification model and outline a more nuanced approach for the risk assessment of intermediate-risk patients. Our main findings were: (1) several echocardiographic parameters related to RV structure and function (RA area, RV end-systolic and end-diastolic areas, RV FAC, TAPSE, degree of TR) correlated strongly with PAH risk strata, with worse parameters seen in intermediate- and high-risk patients; (2) among a panel of echocardiographic parameters, TAPSE and degree of TR were significantly and strongly associated with transplant-free survival; and (3) echocardiography improves the risk stratification of PAH patients, as it allows for the further stratification of intermediate-risk patients using TAPSE and/or degree of TR. This is the first study to our knowledge that demonstrates an added value from conventional echocardiographic measurements to existing multiparametric risk stratification of patients with prevalent PAH receiving stable PAH therapy.
Echocardiography is a non-invasive, widely accessible clinical tool that is suggested as the first diagnostic study when PAH, or generally PH, is suspected [
4,
5,
22]. Once PAH is diagnosed, echocardiography is recommended every 6–12 months and even earlier after changes in therapy or clinical worsening [
4,
5]. Despite this, the role of echocardiography in the risk stratification of patients with PAH has often been underscored and limited to two echocardiographic parameters in conventional risk stratification approaches: RA area [
4,
7] and the presence of pericardial effusion [
4,
7,
8]. Such parameters are indirect manifestations of cardiac dysfunction, and their prognostic value has not been consistent across studies [
23]. In patients with PAH, symptoms and prognosis are largely reflected by RV morphology and function, and its adaptation to increased afterload [
24,
25]. From a pathophysiologic standpoint, elevated afterload has a progressive negative impact on right heart function, ultimately leading to right heart failure from ventriculoarterial uncoupling [
26]. Several studies have demonstrated a strong association between outcomes in PAH cohorts and echocardiographic measurements that reflect RV function, including TAPSE [
13,
14], TAPSE/PASP [
27,
28], LV end-diastolic eccentricity index [
14], degree of TR [
14], global RV longitudinal systolic strain and strain rate [
15,
29], and RV post-systolic strain patterns derived from the mid-basal RV free wall segments [
16]. We confirmed many of these associations (TAPSE, TAPSE/PASP, degree of TR) in our study and showed that their clinical utility can be extrapolated to refine the COMPERA risk stratification approach, which combines clinical, functional, exercise, and hemodynamic parameters to stratify patients into low-, intermediate-, and high-risk for one-year mortality [
6]. In this study, we describe a refined approach to further stratify intermediate-risk patients using echocardiographic parameters.
Risk stratification of patients with PAH is essential for guiding therapy, with the goal of achieving or maintaining a low-risk profile [
3,
4]. However, several studies have shown that most patients, including those treated with dual oral combination therapy, remain in the intermediate-risk category, although it is unlikely that they all share the same mortality risk [
5,
6,
7,
10,
11]. This is important from a clinical standpoint since the management of patients with intermediate risk is not straightforward, unlike that of patients with low-risk who need no further change in therapy or those with high-risk who obviously require more aggressive interventions, such as parenteral therapy or lung transplantation referral [
4,
30]. Therapeutic options for patients who remain in the intermediate-risk category despite dual oral combination therapy with a PDE5-I and an ERA include adding selexipag [
31,
32], switching from PDE5-I to riociguat [
33,
34,
35], initiating parenteral prostanoids [
12] and lung transplantation referral [
12]. Based on this, we believe that the further risk stratification of patients in the intermediate-risk category may help clinicians decide how aggressive subsequent interventions should be. The current study indicates that TAPSE and degree of TR can differentiate patients with preserved cardiac function and better prognosis from those with poor cardiac function and worse prognosis within the intermediate-risk group. Notably, patients in the intermediate-risk group who had both TAPSE ≥ 19 mm and no/trace/mild TR had similar estimated one-year survival (97%) as those in the low-risk group (95%) and thus probably require minimal therapeutic intervention. Likewise, patients in the intermediate-risk group who had both TAPSE < 19 mm and moderate/severe TR had similar estimated one-year survival (56%) as those in the high-risk group (56%) and would require more aggressive intervention.
With the majority of patients remaining in the intermediate-risk category after initial therapy, more recent studies modified existing approaches to provide a more granular risk stratification of patients with PAH. Recent data suggested that stroke volume index at first follow-up following the diagnosis of PAH can discriminate between two survival phenotypes within the intermediate-risk category [
36]. Additionally, a four-strata approach described by COMPERA investigators computes rounded average risk scores using refined cut-off levels for WHO FC, 6MWD, and BNP/NT-proBNP and provides better discrimination compared to the conventional three-strata approach using the same variables [
37,
38]. Another recent study identified a subgroup of intermediate-risk patients with 6MWD ≥ 270 m and TAPSE/PASP ≥ 0.24 mm/mmHg who had significantly better survival compared to other patients in the same risk group [
28]. While these studies allowed for more granular risk stratification, they relied heavily on WHO FC, a very subjective assessment [
39], and on 6MWD, which has questionable validity in CTD-PAH due to comorbid musculoskeletal limitations [
40]. The current study presents a new four-strata approach that allows for better discrimination by incorporating more objectively obtained clinical echocardiographic parameters into the existing COMPERA model. While both TAPSE and degree of TR were used to further stratify intermediate-risk patients, the approach that combined both parameters had the highest discriminatory power, with a C-statistic (0.81) exceeding that of conventional three-strata approaches (COMPERA score C-statistic = 0.62, French Pulmonary Hypertension Registry model C-statistic = 0.64, Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 score C-statistic = 0.73) [
5,
6,
41], and, more importantly, that of novel four-strata risk scores (COMPERA 2.0 score C-statistic = 0.73, Yogeswaran et al. model C-statistic = 0.72) [
28,
37,
38]. A recent study of 102 PAH patients showed that TAPSE/TR velocity and TAPSE/PASP have the potential for dichotomizing intermediate-risk patients into two risk categories [
42]. However, the majority of patients (75%) in this study had incident PAH and were not on PAH therapy, unlike patients included in our study who were already on optimal PAH therapy. This is clinically important, as the management of intermediate-risk patients with incident PAH may be straightforward, unlike that of prevalent PAH patients, who remain intermediate-risk despite receiving PAH therapy.
Our study had a number of limitations. Our cohort was enriched with connective tissue disease-associated PAH, which may limit the generalizability of the findings. Although patients were prospectively enrolled in the registry, the analysis was retrospective in nature and was limited to a relatively small sample size, which limited additional subgroup analyses. Although the COMPERA model includes mixed venous oxygen saturation (MvO2) as one of the parameters used for risk stratification, it was not available for patients in our cohort and hence not included. However, we believe this has minimal effect on our results as the COMPERA model computes an averaged risk for every patient provided that at least two parameters are available, a condition which was satisfied by all patients in our cohort, with the vast majority having at least three parameters. The echocardiographic parameters used in risk stratification are clinically available, yet they are prone to inherent inter-reader variability, especially the degree of TR, which may be under- or overestimated [
43]. A further limitation is that echocardiographic data was collected in different centers with no core measurement and over a 15-year period, with some being obtained before the publication of the Guidelines for Echocardiographic Assessment of the Right Heart in Adults, which standardized right heart echocardiographic evaluation [
22]. Nevertheless, all patients were evaluated in PAH referral centers by expert echocardiographers. Finally, given our sample size and the limited number of subjects reaching the primary outcome during the follow-up period, we could not run extensive multivariate Cox regression analysis and adjust for all potential confounders.