Pulmonary arterial hypertension (PAH) is a chronic pulmonary vascular disease characterized by elevated pulmonary vascular resistance (PVR) and pulmonary arterial (PA) pressure (PAP). Currently, the incidence and prevalence of PAH are approximately 5/million and 25/million, respectively (Hoeper et al., 2016). According to the updated 2022 European Society of Cardiology/European Respiratory Society (ESC/ERC) guideline, PAH is pre-capillary pulmonary hypertension defined as mean PAP (mPAP) > 20 mmHg, PVR >2Wood Units and PA wedge pressure (PAWP) ≤15 mmHg as measured by right heart catheterization (RHC) (Humbert et al., 2022). Clinically, PAH is divided into the following subgroups based on etiology, including idiopathic PAH (IPAH), heritable PAH, drug- and toxin-induced PAH, PAH associated with other conditions [such as connective tissue disease (CTD), congenital heart disease (CHD)], PAH with features of venous/capillaries involvement, and persistent PAH of the newborn (Humbert et al., 2022). At present, the pathogenesis of PAH remains unclear, and pulmonary arterial remodeling is an important pathological hallmark. Similar to malignancy, patients with PAH have an extremely poor prognosis (Ruopp and Cockrill, 2022). Previous studies demonstrated that the median survival of treatment-naive patients with IPAH was only 2.8 years, and the 1- and 5-years survival rates were 68% and 34%, respectively (D'Alonzo et al., 1991). During the past few decades, advances in understanding of the pathogenesis of PAH have led to significant progress in PAH-targeted medications, including phosphodiesterase-5 inhibitors (PDE-5i), endothelin receptor antagonists (ERAs), prostacyclin analogues and prostacyclin receptor agonists (PGI2), and soluble guanylate cyclase stimulators (sGCs). Notably, although targeted drugs improve the symptoms and haemodynamics, the 5-years survival rate of PAH has only increased to over 60% (Farber et al., 2015), which has not yet been satisfied.

Elevated PVR and PAP increase the right ventricular (RV) afterload and promote adaptive or non-adaptive RV remodeling, which triggers RV dysfunction and right heart failure. Studies have revealed that RV function is closely related to functional class and prognosis in patients with PAH, and deteriorating cardiac function portends a poor prognosis. To our knowledge, there were significant survival differences among different subgroups of PAH. The survival of patients with IPAH was inferior to that of patients with PAH associated with CHD (PAH-CHD) (Manes et al., 2014), but superior to that of patients with CTD-associated PAH (CTD-PAH) (Chung et al., 2010; Chung et al., 2014; Ramjug et al., 2017). In addition, significant survival differences were also observed between different subtypes within the same subgroup. Chung and colleague confirmed that patients with systemic sclerosis (SSc)-associated PAH (SSc-PAH) have a higher mortality rate than those with CTD other than SSc-associated PAH (Chung et al., 2010). In the PAH-CHD cohort, when compared with patients with Eisenmenger syndrome (ES) or PAH-CHD associated with systemic-to-pulmonary shunts (SPs), patients with small defects (SDs) or PAH after defect correction (CDs) had the worse prognosis (Manes et al., 2014). Previous studies have shown that diverse RV function and response to PAH-targeted therapy are associated with differences in prognosis between patients with CTD-PAH and patients with IPAH (Rhee et al., 2015; Ramjug et al., 2017). In China, PAH-CHD and IPAH are two prevalent types of PAH, and their baseline right heart function and response to targeted drugs are less studied. Given that RV dysfunction are closely associated with poor prognosis, we intend to explore baseline RV function and its response to targeted agents between IPAH and PAH-CHD.

Right heart failure is a life-threatening complication of PAH and is associated with increased mortality. In the present study, we retrospectively analysed the differences in baseline RV function and response to targeted therapy between patients with IPAH and patients with PAH-CHD admitted to our centre over the past 10 years. First, the average age of these enrolled population was 36.23 years old and female was predominant. The overall female-to-male ratio was 2.37:1, and the ratio in IPAH group was approximately 1.95:1, which was similar to what we observed in COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) Registry (Hoeper et al., 2013).

The normal right ventricle is thin-walled, low afterload, and high-compliance distinct from the left ventricle. Anatomic and functional characteristics determine that the right ventricle is more capable of accommodating the volume overload rather than pressure overload (Edward et al., 2022). In PAH, as a consequence of persistently elevated PAP, the RV afterload and wall stress are increased resulting in RV hypertrophy, dilation, and dysfunction under suitable conditions, and the severity is affected by the duration of the pressure overload. Interestingly, abundant literature demonstrated that RV structure and function in people lacking cardiopulmonary disease vary with age, gender, race, exercise (Kawut et al., 2011; Cornwell et al., 2020; Thenappan and Weir, 2020; Edward et al., 2022). Therefore, it is easy to understand the divergent responses of RV to PH subtypes with different pathogenesis and pathophysiology. For example, Emami and colleagues found that patients with IPAH had better RV function compared to those with PH secondary to chronic heart failure (PH-HF) (Emami et al., 2020). This study showed that patients with IPAH had higher peak systolic velocity of tricuspid annulus, higher dp/dt, and better RV free wall stiffness, but other RV parameters such as TAPSE and FAC are only slightly increased without reaching statistical significance. In subgroup analysis of PAH, multiple studies have demonstrated that patients with SSc-PAH had worse resting and reserve RV function than patients with IPAH (Overbeek et al., 2008; Tedford et al., 2013; Hsu et al., 2016; Hsu et al., 2018). This RV dysfunction in SSc-PAH was associated with impaired intrinsic myocardial contractility, decreased calcium cycling, higher RV fibrosis and diastolic stiffness, and RV-PA decoupling (Tedford et al., 2013; Hsu et al., 2016; Hsu et al., 2018).

In our study, the mPAP in IPAH group was significantly lower than that in PAH-CHD group, but a higher baseline PVR implied more severe pulmonary vascular disorders in the IPAH cohort. Pericardial effusion, a relatively common complication of PAH, is associated with increased mortality (Fenstad et al., 2013; Shimony et al., 2013; Chandel et al., 2021). In this study, the incidence of pericardial effusion (40.5%) in patients with IPAH was similar to that in Shimony’s study (47.1%), which may be related to RV dysfunction and subsequent increased right atrial filling pressure (Shimony et al., 2013). Subsequent analysis showed that the RV function (TAPSE, RVFAC) in patients with IPAH was significantly inferior to that in patients with PAH-CHD. As discussed above, RV structure and function are subject to multiple factors, and following conditions may account for the difference in RV function at baseline: firstly, the clinical manifestations in patients with IPAH are non-specific with insidious onset, and some patients present with RV dysfunction or even decompensation at initial diagnosis, which is confirmed by the higher proportion of severe RV dysfunction in the IPAH group in our study. Secondly, pathogenesis participates in this difference. Anomalous systemic-to-pulmonary shunt increases volume-load or pressure-load, which plays an important role in the development of PAH-CHD. In the early stage of PAH-CHD, PVR is only moderately elevated. As PAH-CHD progresses, which may take decades, irreversible pulmonary artery lesions such as plexiform lesions and necrotising arteritis appear, leading to loss of pulmonary vascular beds and subsequent progressive elevation of PVR and PAP with bidirectional or reverse shunt (Van der Feen et al., 2017). In the long-term chronic course of PAH-CHD, right ventricle can better adapt to the elevated afterload and maintain better RV function (Giusca et al., 2016; Brida and Gatzoulis, 2018). Whereas, the mechanism of RV dysfunction in IPAH is more mysterious and complex, including genetics, afterload overload, metabolic transformation, myocardial ischemia, and other aspects (van der Bruggen et al., 2016; Sun et al., 2017; Sanz et al., 2019; Sree et al., 2021). Finally, RV histological features contribute to these differences. Adaptive RV remodelling in PAH-CHD (such as ES) patients is characterized by RV hypertrophy, increased RV contractility, lower RV fibrosis and RV diastolic stiffness (Giusca et al., 2016; van der Bruggen et al., 2017). However, the adaptive RV remodelling in IPAH patients is consistent with a combination of RV hypertrophy, increased RV contractility, higher RV fibrosis and RV diastolic stiffness (van der Bruggen et al., 2017). These features suggest that IPAH patients have poor RV adaptation and are more susceptible to deteriorate from RV hypertrophy to RV failure. Notably, patients with PAH-CHD who met operative indications at initial diagnosis were not included in this study, and this design may narrow the actual gap in baseline RV function between the two cohorts.

At present, assessing the severity of PAH patients by multiparameter risk stratification is an important principle for selecting treatment strategies. A large number of literature has demonstrated that PAH-specific medications, especially combined therapy, improve activity tolerance, quality of life, hemodynamics, and RV structure and function in patients with IPAH and patients with PAH-CHD (D’Alto et al., 2020; Fathallah and Krasuski, 2018; Ruopp and Cockrill, 2022; Vonk et al., 2022). Given that vasodilators are expensive, PAH patients often bear a heavy economic burden. Therefore, we dynamically adjusted treatment strategy based on contemporaneous guidelines and economic conditions. In our study, patients with IPAH had a higher proportion of combination therapy and parenteral prostacycline than patients with PAH-CHD. Targeted therapy remarkably improved overall 6 MWD, WHO FC, PASP, RV function, and survival. Further subgroup analysis showed that vasodilator therapy substantially improved hemodynamic status and RV function in patients with PAH-CHD, and 36 patients successfully repaired the defect. However, although survival in IPAH cohort was improved, RV function was only slightly increased and did not have statistical difference, and 6 MWD even witnessed a downward trend, which was inconsistent with previous studies. To our knowledge, targeted agents relieve symptoms by dilating PA and reducing RV afterload. Patients’ response to targeted therapy was influenced by RV remodelling and treatment strategies, which had also been observed in other subtypes of PH. For instance, patients with CTD-PAH had a worse therapeutic response than those with IPAH (Rhee et al., 2015; Argula et al., 2017; Hsu et al., 2018). Goh and colleagues evaluated RV remodelling by cardiac magnetic resonance (CMR) and demonstrated that the high-volume-low-mass (HVLM, i.e., maladaptive RV remodelling) group had a worse prognosis than the low-volume-low-mass (LVLM, i.e., adaptive RV remodelling) group (Goh et al., 2022). After treatment, a higher proportion (73.5%) of LVLM patients remained in this group, and only 17.4% of HVLM patients converted to LVLM. In our study, IPAH patients had more severe baseline RV dysfunction, RV-PA coupling, and pulmonary vascular disorders. Considering that the baseline RV function was not matched between IPAH and PAH-CHD, we matched the RV function and subsequently analysed the patients’ response to targeted drugs. The results indicated that targeted drugs improved WHO FC and TAPSE in patients with severe RV dysfunction (i.e., TAPSE<12 mm), and there was no significant difference in ΔTAPSE and ΔRV FAC between PAH-CHD and IPAH. Notably, for patients with non-severe RV dysfunction (i.e., TAPSE≥12 mm), patients with PAH-CHD had a better response to treatment than patients with IPAH. The limited effect of targeted agents on PA dilation may partially account for the different treatment responses between two cohorts. Additionally, deterioration of treatment-naive PAH patients has progressed over time. Targeted therapy effectively increases the time to clinical deterioration and improves survival in IPAH patients. However, the follow-up period in our study was relatively longer (up to 132 months), it is necessary to further verify whether the improvement in RV function in IPAH patients receiving treated therapy will continue to improve in the next few years.

Lung transplantation is effective in treating end-stage PAH. However, given the difficulty in obtaining donors and long waiting time, patients with a high or intermediate–high risk of death or with an inadequate response to treatment should be considered as lung transplantation candidates earlier. Several small sample studies (Boucly et al., 2021; D’Alto et al., 2020) have proved that triple combination therapy including parenteral prostacyclin significantly increases transplant-free survival and reverses RV remodelling, suggesting that this may be a good transition for critical patients.

This study still had the following limitations. Firstly, this was a single-center retrospective study. During long-term follow-up, patients’ treatment strategies, especially combination therapy, were dynamically adjusted according to contemporaneous guidelines and economic condition, and this study reflected the effectiveness of the overall treatment strategy. Secondly, we chose conventional parameters to evaluate RV function. Emerging evidence demonstrated that CMR was also effective evaluation tools, and TTE combined with these new indicators may have more important value. Finally, the included population was relatively small, and there were large differences between different groups after matching RV function. Prospective studies with larger populations will be required in the future.

In conclusion, we analysed RV function and its response to PAH-targeted therapy between IPAH and PAH-CHD cohorts. Compared with patients with PAH-CHD, patients with IPAH hade worse baseline RV function, unfavourable prognosis, and inadequate response to targeted treatment. Patients with inadequate response to treatment may be considered as candidates for lung transplantation earlier.