FormalPara Key Points

Pulmonary arterial hypertension (PAH) is a progressive disease with a high mortality rate despite advances in therapy.

Currently, therapies target traditional pathways such as nitric oxide, prostacyclin, thromboxane A2, and endothelin-1.

Several alternative pathways have been targeted in PAH patients and have shown to improve patient hemodynamics and functional class in patients with PAH.

1 Introduction

Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (mPAP) of > 20 mmHg by right heart catheterization. PH is classified into five separate groups: pulmonary arterial hypertension (PAH, Group1), PH due to left heart disease (PH-LHD, Group 2), PH due to lung disease (Group 3), PH due to obstruction of the pulmonary artery (Group 4), and PH due to multifactorial mechanism or unclear cause (Group 5) [Table 1] [1,2,3].

Table 1 Classification of pulmonary hypertension (adapted from Simonneau et al. [2])
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This article focuses on the pathophysiology and treatment of PAH. PAH is defined by an mPAP of > 20 mmHg, pulmonary capillary wedge pressure (PCWP) ⩽ 15, and pulmonary vascular resistance (PVR) ⩾ 2 Wood units. There are several subgroups of PAHs based on etiology: idiopathic PAH, which accounts for the majority of cases; heritable PAH, drug and toxin-induced PAH; and PAH associated with other conditions such as human immunodeficiency virus (HIV), portal hypertension, connective tissue disease, congenital heart disease and schistosomiasis (Table 1).

According to the current data, PAH is associated with a better prognosis compared with other forms of PH, primarily because of the PAH-specific treatment [4]. The incidence of PAH is estimated to be up to 2.4 cases per million per year, whereas the prevalence is estimated to be up to 15 cases per million per year [5, 6]. However, despite the progress in treatment, the mortality rate remains high, with a 7-year survival rate of only 50%.

Age, sex, and underlying cause of PAH affect the prognosis. Higher mortality rates were reported in male patients with idiopathic and hereditary PAH, males over 60 years of age, patients with systemic sclerosis-associated PAH, portopulmonary hypertension, and patients with bone morphogenetic protein receptor 2 (BMPR2) mutation. Symptoms and functional class of the patients can also affect the outcomes based on some studies; however, exercise capacity with the 6-min walk test (6MWT) and cardiopulmonary exercise testing (CPET) can also help determine prognosis [7].

2 Pathophysiology

Regardless of the underlying etiology of PAH, the pathological features are similar and include endothelial dysfunction, endothelial and smooth muscle remodeling, and pulmonary artery smooth muscle cell proliferation. Multiple pathways are involved in the pathophysiology of PAH, including nitric oxide (NO), prostacyclin (PGI2), thromboxane A2 (TXA2), and endothelin-1 (ET-1) [5, 8, 9].

Endothelial cells produce NO, which diffuses to the underlying vascular smooth muscles, stimulating soluble guanylyl cyclase and increasing smooth muscle cyclic guanosine monophosphate (cGMP), resulting in pulmonary vasodilation. NO also inhibits smooth muscle cell proliferation and the aggregation of platelets. It is believed that there is a reduction in the bioavailability of NO in PAH, which was previously assumed to be caused by reduced expression of NO synthase (eNOS), which converts l-arginine to NO; however, recent studies have shown persistent eNOS activation in mice models of PAH. Consequently, reactive oxygen species (ROS), mainly tetrahydrobiopterin, have been implicated in endothelial dysfunction, vasoconstriction, and vascular remodeling due to enzymatic uncoupling of eNOS [5, 10, 11].

PGI2 is produced in endothelial cells from arachidonic acid, which increases smooth muscle cyclic adenosine monophosphate (cAMP), resulting in pulmonary vasodilation. In PAH, TXA2 may cause vasoconstriction and proliferation [5, 12].

ET-1 is a peptide produced by endothelial cells that causes vasoconstriction. ET-1 acts on two receptors; ETA is located in the pulmonary artery smooth muscles causing vasoconstriction, while ETB is located in the vascular smooth muscles, also causing vasoconstriction, but is also located on endothelial cells, resulting in activation of NO and PGI2, leading to vasodilation. In PAH patients, there is more expression of ETA and ETB in smooth muscles, causing vasoconstriction [5, 13].

3 Management

Therapies for PAH have progressed in the last two decades, with more medication targeting different pathways and resulting in more effective outcomes. Based on the current literature, a number of variables influence the prognosis of the disease, allowing us to risk-stratify patients into low, intermediate, and high mortality risk. The main goal in treating PAH patients now is to get patients to a low-risk classification (Table 2) [5, 14, 15].

Table 2 Risk stratification of pulmonary arterial hypertension (adapted from the 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension [15])
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Available treatments include phosphodiesterase-5 inhibitors (PDE5Is), prostacyclin analogs, prostacyclin receptor agonists, soluble guanylate cyclase stimulators (sGCs), and endothelin receptor antagonists (ERAs) (Fig. 1) [5]. In this paper, we discuss current and novel drugs for treating PAH. Advances in science will help to discover pathways involved in the development of PAH, and targeting those in the next era in treating PAH (Fig. 2) [16].

Fig. 1
figure 1

Current treatments for pulmonary arterial hypertension. The pathophysiology and current therapeutic targets of pulmonary arterial hypertension (adapted from the 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension [15]). NO nitric oxide, PDE5 phosphodiesterase 5, sGC soluble guanylate cyclase, cGMP (cyclic) guanosine monophosphate, GTP guanosine-5′-triphosphate, IP receptor prostacyclin I2 receptor, cAMP cyclic adenosine monophosphate, ESC European Society of Cardiology, ERS European Respiratory Society

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Fig. 2
figure 2

Novel pathways in treating pulmonary arterial hypertension. The figure shows alternative pathways discussed in this paper in treating PAH. Various mechanisms contribute to the development of PAH, such as inflammation, vasoconstriction, abnormal endothelial and smooth muscle cell growth, proliferation, and apoptosis (created with BioRender). BMP bone morphogenetic protein, BMPR-II BMP receptor type 2, EC endothelial cells, PDGF platelet-derived growth factor, PDGFR PDGF receptor, SMC smooth muscle cells, TGF-β transforming growth factor-β, TPH1 tryptophan hydroxylase 1, VIP vasoactive intestinal peptide, VPAC vasoactive intestinal peptide receptor

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3.1 Current Therapies

Perhaps the most widely prescribed drug in PAH is the PDE5I, including sildenafil and tadalafil. This works on the NO pathway, resulting in vasodilation and antiproliferative effects. The SUPER trial, a randomized, placebo-controlled trial, included 278 PAH patients assigned to either placebo or different doses of sildenafil three times daily. Functional class, mean pulmonary artery pressure, and PVR improved after 12 weeks of the trial in the sildenafil arm. Tadalafil was US FDA-approved in 2009 and has a longer half-life, therefore it can be prescribed once daily. The PHIRST trial was a double-blind, randomized, placebo-controlled trial that included 405 PAH patients. In 16 weeks, 40 mg of tadalafil improved exercise capacity and reduced time to clinical worsening in patients who were not receiving treatment or patients taking background bosentan [17, 18]. Riociguat, a sGC, is another agent that targets the NO pathway. The CHEST-1 trial, which included 261 patients, was a phase III, randomized, double-blinded trial. After 16 weeks, riociguat was found to improve functional capacity and PVR [19]. A subsequent non-blinded study suggested that switching to riociguat from a PDE5I benefited patients with functional class III receiving background ERA, although there was no improvement in brain natriuretic peptide (BNP) [20].

FDA-approved ERAs for PAH include bosentan, ambrisentan, and macitentan. Thirty-two patients with functional class III PAH were randomized to receive bosentan or a placebo in a double-blind, randomized, placebo-controlled trial. Following 12 weeks of follow-up, the bosentan group showed improvement in 6-min walk distance (6MWD) [21]. As the EARLY trial demonstrated, the benefit was also seen in PAH patients with functional class II [22]. The ERA class also includes ambrisentan. Following a 12-week trial where patients were randomized to either ambrisentan or placebo, ambrisentan improved 6MWD, time to clinical worsening, and functional class [23]. Macitentan is another FDA-approved ERA drug. Patients with PAH were randomly assigned to either macitentan 3 or 10 mg or a placebo in the SERAPHIN trial. Primary endpoints were death, clinical worsening, initiation of intravenous or subcutaneous prostanoids, atrial septostomy, and lung transplantation. A primary endpoint occurred in 46.4% of placebo patients, 38.0% of patients in the macitentan 3 mg group, and 31.4% of patients in the macitentan 10 mg group. The hazard ratio for the macitentan 3 mg dose compared with placebo was 0.70, with a p value of 0.01, and the hazard ratio for the macitentan 10 mg dose compared with placebo was 0.55, with a p value of < 0.001. The study was positive regardless of whether the patient was receiving prior therapy for PAH [24].

Prostanoid drugs were the first available PAH-specific therapy, targeting the prostacyclin pathway. Intravenous, subcutaneous, and inhaled forms of prostanoids have all not only had their benefits but also their challenges. Intravenous epoprostenol was the first agent to be studied and approved for PAH, having demonstrated improved symptoms and decreased mortality. Treprostinil has been shown to improve 6MWD through intravenous, subcutaneous, and inhaled forms. Oral treprostinil went on to become the first oral prostanoid to be FDA-approved, after FREEDOM M and FREEDOM-EV showed that oral treprostinil improved 6MWD as monotherapy and reduced time to clinical worsening when used in combination with either an ERA or PDE5I [25,26,27]. Selexipag is a prostacyclin receptor agonist that was studied in the GRIPHON trial. In this study, a composite of death from any cause or complications related to PAH occurred in 41.6% and 27.0% of those patients in the placebo group versus those in the selexipag group [28].

Treatment of PAH has progressed in recent years to include combination therapy that targets the above pathways. Trials such as AMBITION, GRIPHON, and FREEDOM-EV have demonstrated the effectiveness of dual combination therapy in PAH patients. How and when to start triple therapy is less well described or studied.

3.2 Novel Therapies

3.2.1 Transforming Growth Factor-β Pathway

BMPs are part of the transforming growth factor (TGF)-β family; unopposed TGF-β signals happen when we have a loss of function of the BMPR2 genes, which is essential in regulating vascular cell apoptosis and maintaining normal function of the endothelium. When BMPR2 is suppressed, there is unopposed signaling of TGF-β, resulting in proliferation of the vascular cells and remodeling [29, 30]. Sotatercept is a novel drug that works on the BMPR2 gene and the TGF-β pathway. By working as a trap ligand of the TGF-β pathway, it helps to suppress TGF-β and enhances the BMPR2. In the phase II PULSAR trial, PVR was reduced by 34% in patients treated with sotatercept when compared with placebo. 6MWD and NT-pro-BNP were also reduced. Thirty-seven percent of patients were receiving background parenteral treatment and 56% were receiving triple therapy. The STELLAR trial, a phase III, multicenter, double-blind trial, included 323 patients who were receiving stable background therapy. Patients were randomized to receive sotatercept or placebo. The primary endpoint was change in 6MWD at 24 weeks. At 24 weeks, the difference in change in the 6MWD between the sotatercept and placebo groups was + 40.8 m (95% confidence interval [CI] 27.5–54.1; p < 0.001) in favor of sotatercept. Sotatercept also had a significant difference in time to first death or non-fatal clinical worsening events. At week 24, the sotatercept group showed significant improvement in NT-proBNP levels, functional class, and PVR. Furthermore, sotatercept had more adverse events, such as an increase in hemoglobin, thrombocytopenia, telangiectasia, epistaxis and dizziness, when compared with the placebo group [31,32,33,34].

3.2.2 Platelet-Derived Growth Factor Pathway

Platelet-derived growth factor (PDGF) is reported to have a role in PAH. PDGF acts through transmembrane tyrosine kinase receptors, and when the PDGF is overexpressed, it leads to proliferation of the pulmonary artery smooth muscles. It has been reported that patients with PAH have increased signaling of the PDGF pathway. Imatinib, a tyrosine kinase inhibitor, has been studied in PAH [29, 35, 36]. In a phase II, randomized, double-blinded trial that included 59 patients with PAH, with a primary endpoint of change in 6MWD and safety and tolerability, resulted in no significant change in 6MWD but significant reduction of PVR in the treatment arm. This study suggested that imatinib was probably safe and well tolerated in PAH patients and provided a reference for further studies [37]. The IMPRES trial was a phase III trial aiming to assess the effect of imatinib in PAH patients; 202 patients were included, with PVR ≥ 10 Wood units and receiving two or more therapies for PAH. The primary endpoint was change in 6MWD. After 24 weeks of follow-up, oral imatinib significantly helped to reduce 6MWD and PVR. However, the study showed a 44% incidence of serious adverse events, including a number of patients having subdural hematoma, and a high rate of discontinuations; thus far, imatinib has not been FDA-approved for PAH treatment [38]. A phase III trial (IMPAHCT, NCT05036135) that is currently recruiting patients is studying dry powder imatinib in patients with PAH. This study is interesting because imatinib will likely not have the systemic adverse effects that were observed in the IMPRES study. The primary endpoint of this trial was to establish a dose for phase III. The primary endpoint of the phase III part of the trial is the change in 6MWD at 24 weeks. Alternative formulations of imatinib are also under study, such as an enteric-coated version [39].

Inhaled seralutinib is a unique small molecule inhibitor of the PDGF receptor (PDGFR), colony-stimulating factor 1 receptor (CSF1R), and c-KIT. Inhaled seralutinib is also in clinical development and is being studied in PAH [40]. The phase II TORREY trial showed that patients treated with seralutinib had a statistically significant placebo-corrected improvement in PVR of 14.3%. A phase III study is being planned.

3.2.3 Prostacyclin Pathway

Ralinepag is an immediate-release oral drug acting as a non-prostanoid prostacyclin receptor agonist that acts on the prostacyclin pathway, similar to selexipag but with a longer half-life. Ralinepag was studied in a phase II trial of 61 patients. The study showed promising findings of significant improvement in 6MWD and significant reduction of PVR in patients receiving monotherapy or dual therapy compared with placebo [31, 41, 42]. Several trials are currently underway with ralinepag. The ADVANCE OUTCOMES trial (NCT03626688) is a phase III trial that is currently recruiting, and is intending to recruit 700 patients. This is a multicenter, randomized, double-blinded trial with a primary endpoint of time to clinical worsening. Patients will be randomized to either placebo or ralinepag in addition to standard of care.

3.2.4 Other Pathways

Udenafil is a long-acting PDE5I that has a favorable safety profile. In a phase II trial, patients were randomized to three groups—placebo, udenafil 50 mg or udenafil 100 mg. Hemodynamics were monitored for 4 h after drug administration. The results showed a reduction in mPAP for both doses and a reduction in PVR, with statistical significance in the 50 mg arm [43]. Chang et al. studied udenafil in a 16-week, randomized, double-blinded, phase IIb trial. Sixty-three patients were randomized to either placebo or udenafil 50 mg. Patients taking udenafil significantly improved in 6MWD, and udenafil had a good safety profile [44].

Serotonin pathways have been implicated in the pathophysiology of PAH. Serotonin has been found to promote pulmonary vascular smooth muscle proliferation. Rodatristat ethyl works on the serotonin pathway as a tryptophan hydroxylase 1 inhibitor, which in turn reduces the release of serotonin [45]. The ELEVATE 2 trial (NCT04712669) is a phase II, randomized, double-blind, placebo-controlled trial that is currently recruiting. The study’s goal is to include 90 patients and to randomize to either rodatristat ethyl 300 mg twice daily or rodatristat ethyl 600 mg twice daily compared with placebo, in addition to standard of care in both arms. The primary outcome is the change in PVR at 24 weeks.

The vasoactive intestinal peptide (VIP) analog pemziviptadil (PB1046) has been studied in PAH, however the studies were terminated due to poor recruitment during the coronavirus disease 2019 (COVID-19) pandemic [16].

The optimum dose of macitentan is currently under investigation. In the phase III UNISUS trial (NCT04273945), 900 patients will be randomized to receive either 10 mg once daily or a matching placebo of macitentan 37.5 mg for 4 weeks (up-titration) and a matching placebo of macitentan 75 mg after that. The primary endpoint is time to first morbidity and mortality event, defined as all-cause death, PAH-related hospitalization, or PAH disease progression [46].

A combination pill has not been previously studied in PAH. A phase III trial (NCT03904693) is planned and is expected to be a randomized, double-blind study with a target of 187 PAH patients looking at a combined pill comprising of macitentan and ambrisentan compared with both drugs being taken individually. The primary endpoint is changes in PVR at 16 weeks.

Other drugs such as metformin are thought to be helpful in PAH patients. Insulin resistance is thought to be a risk factor for PAH. Metformin affects the production of NO and ROS and thus helps prevent proliferation and remodeling. However, the studies are in the recruitment phase.

4 Conclusion

Despite advances in the treatments of PAH, the mortality rate remains unacceptably high. Currently, three pathways are effectively targeted. However, the emergence of a number of new targets currently in active clinical trials is very encouraging and suggests improved outcomes for patients with PAH in the near future.