Pulmonary arterial hypertension (PAH) is a condition characterized by a complex process of vascular dysfunction, smooth muscle cell, and remodeling of small pulmonary vessels, leading to increased pulmonary vascular resistance (PVR) and pulmonary artery (PA) pressure.

In the latest (2022) European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines for the diagnosis and treatment of pulmonary hypertension (PH),1 PAH is classified as group 1 PH, comprising subgroups of conditions with similar pathophysiological mechanisms, clinical presentation, hemodynamic characteristics, and therapeutic management. The subgroups are listed in Table 1.

Hemodynamic parameters are key in defining and classifying PH. By definition, PAH, similar to chronic thromboembolic PH, is classified as pre-capillary PH as both primarily affect the pre-capillary pulmonary vasculature. The absolute threshold for defining PH was first set at a mean PA pressure (mPAP) ≥25 mmHg in a somewhat arbitrary fashion in the first World Symposium for PH (1973). Since then, real-world evidence provided by large retrospective studies and registries has led to a revision of this figure. The latest ESC/ERS guidelines define PH as mPAP >20 mmHg at rest, defining group 1 PAH as having both PVR <2 Wood units (WU) and PA wedge pressure (PAWP) <15 mmHg, thus excluding a predominant postcapillary component. This distinction in essential, considering the different therapeutic approaches for these subtypes.

PAH is a progressive disease, presenting with symptoms of incapacitating fatigue causing marked loss of quality of life, eventually culminating in right ventricular (RV) failure and death.

Targeted therapies have been developed in recent decades, effectively changing the disease's natural history and improving prognosis. Nevertheless, it remains a challenging condition, with significant morbidity and mortality. Over the last few years, new targeted therapies have appeared based on a deeper understanding of the pathophysiology underlying PAH.

In a rapidly evolving field, this article aims to review current disease management, focusing on pathophysiology, risk stratification, and therapeutic approaches according to the latest guidelines and most recent clinical trials.

The annual incidence of PAH in Europe is estimated to be approximately six cases per million individuals per year, with a prevalence of about 50 cases per million.2 It predominantly affects young women, particularly in the case of heritable PAH, with a female-to-male ratio of 2:1. Mean age at diagnosis ranges between 30 and 60 years.3

Mutations in the gene encoding bone morphogenetic protein receptor type 2 (BMPR2), a member of the transforming growth factor beta (TGF-β) superfamily, have been identified as the most frequent cause of heritable PAH.4 In asymptomatic carriers of a BMPR2 mutation, the annual incidence of PAH is 2.3%, and females have 3–4 times higher risk.4

Several other conditions are associated with PAH. Schistosomiasis is thought to be the leading cause of PAH globally, owing to its high prevalence in low- and middle-income countries; it is estimated to affect more than 230 million people worldwide, of whom 10% develop hepatosplenic disease, 5% of whom may develop PAH.5

The prevalence of PAH in patients with connective tissue disease is considerable, ranging from around 7% in patients with systemic sclerosis (SSc)6 to 0.5–17% in systemic lupus erythematosus.7 Around 1% of HIV carriers may develop PAH. Congenital heart disease and portal hypertension are also important risk factors for developing PAH.8 Its prevalence does not appear to be influenced by the severity of portal hypertension or liver disease, as it occurs in 2–6% of patients with portal hypertension. Additionally, several drugs and toxins are associated with the development of PAH (Table 2).

PAH is the result of a complex process involving multiple cellular signaling pathways, which not only develop and work in parallel but also feed one another, perpetuating the vicious cycle underlying pulmonary vascular remodeling (Figure 1).

Figure 1.

Pathophysiology and current therapeutic targets of pulmonary arterial hypertension. cAMP: cyclic adenosine monophosphate; cGTP: cyclic guanosine triphosphate; DLCO: diffusion capacity of the lung for carbon monoxide; ERA: endothelin receptor antagonist; GMP: guanosine monophosphate; GTP: guanosine triphosphate; NO: nitric oxide; PCA: prostacyclin analog; PDE-5: phosphodiesterase 5; PGI2: prostacyclin; PRA: prostacyclin receptor agonist; sGC: soluble guanylate cyclase.

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Three main pathologic processes can be identified: vasoconstriction, thrombosis, and remodeling.9 Histopathologic analysis of biopsy tissue and explanted lungs has lead to a deeper understanding of the disease process (Figure 2).

Figure 2.

Histopathology of vascular changes of pulmonary hypertension in explanted lungs. (a) Muscular hypertrophy of the media and proliferation of intimal cells narrow the lumen of a pulmonary artery branch; adventitial fibrosis can also be detected; (b) an artery shows concentric laminar fibrosis of the intima, imparting an onion skin-like appearance to the vessel profile; (c) a pulmonary artery lumen is fully occluded; (d) the wall of a small artery is replaced by fibrin and inflammatory cells, causing loss of its architecture, in this example of necrotizing vasculitis; (e–g) a glomeruloid network of small vascular channels, the hallmark of plexiform lesions, can be seen arising from muscular arteries; (h) angiomatoid lesions, characterized by dilated and convoluted vessels with a thin wall, can be seen distal to a plexiform lesion (right corner).

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Hemodynamics is the basis for PH characterization; however, diagnosis relies on exploration of the overall clinical context and findings from complex multisystemic investigations.

The first step in diagnosing PAH is clinical suspicion of PH. Unexplained fatigue, albeit highly nonspecific, is often the initial manifestation. Throughout disease progression, symptoms will appear with progressively less exertion. Other symptoms may be present and point toward the primary etiology. Physical examination may also reveal signs that aid in identifying the underlying cause of PH (Figures 3–5). Cardiac auscultation findings may strengthen suspicion with specific findings (Figure 6). Signs indicating RV failure tend to appear in the later stages of PAH, necessitating prompt medical intervention.

Figure 3.

Common symptoms suggesting pulmonary hypertension and rare symptoms suggesting pulmonary artery dilation (and thoracic compression syndrome). WHO-FC: World Health Organization functional class.

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Figure 4.

Left: clinical signs suggesting right ventricular failure; right: signs suggesting possible underlying etiologies of pulmonary arterial hypertension. CHD: congenital heart disease; CTEPH: chronic thromboembolic pulmonary hypertension; GERD: gastroesophageal reflux disease; HHT: hereditary hemorrhagic telangiectasia; PDA: patent ductus arteriosus; PPHTN: portopulmonary hypertension; PVOD: pulmonary veno-occlusive disease; RV: right ventricular; SSc: systemic sclerosis.

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Figure 5.

Clinical signs suggesting pulmonary hypertension and right ventricular backward failure. RV: right ventricular.

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Figure 6.

Cardiac auscultation findings suggestive of pulmonary hypertension. PH: pulmonary hypertension; PR: pulmonary regurgitation; TR: tricuspid regurgitation.

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An initial assessment should include a comprehensive medical and family history, a thorough physical examination, blood tests, and a resting electrocardiogram. Electrocardiographic findings associated with PH include P pulmonale (tall, peaked P waves), right bundle branch block, and voltage criteria for right ventricular hypertrophy.25

The second step is detecting a high likelihood of PH, through noninvasive lung and cardiac testing. Echocardiography plays a crucial role in the assessment of patients with suspected PH, offering valuable insights into both the probability of PH and potential underlying cardiac abnormalities. This noninvasive imaging modality is a cornerstone of the initial assessment, aiding in the identification of key hemodynamic parameters and structural changes indicative of PH. Direct measurements such as peak tricuspid regurgitation velocity, together with other indirect parameters, enable the probability of PH to be determined (Table 3). The size and respirophasic variation of the inferior vena cava, right atrial area, PA diameter, and RV function parameters, including the tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) ratio, offer valuable information regarding the severity and progression of PAH. Moreover, echocardiography serves as a comprehensive tool for identifying underlying cardiac disorders that may contribute to PH. For instance, the presence of congenital heart disease such as atrial or ventricular septal defect can lead to pulmonary vascular remodeling and subsequent PH. Similarly, left heart disease, including valvular abnormalities or ventricular dysfunction, may result in elevated pulmonary pressures due to increased pulmonary venous congestion, indicating a postcapillary component.

Chest radiograph findings such as enlargement of the right heart and pulmonary artery silhouette are consistent with PAH, but their presence is not ubiquitous.

Pulmonary function testing (PFT), with forced spirometry, plethysmography, diffusion capacity of the lung for carbon monoxide (DLCO), and arterial blood gas analysis is essential in identifying underlying pulmonary disease. In PAH, PFT is usually normal or may show mild abnormalities,26 whereas more severe abnormalities can be found in patients with PAH associated with congenital heart disease and PH associated with lung disease.27 DLCO is typically slightly reduced; severe reduction (<45% of predicted value) may suggest the presence of venous/capillary involvement (pulmonary veno-occlusive disease [PVOD] or pulmonary capillary hemangiomatosis [PCH]). Risk factors like scleroderma or exposure to organic solvents, or group 3 PH associated with emphysema or interstitial lung disease, should be considered.

PaO2 is generally normal or slightly reduced.28 Severe reduction may indicate structural heart disease such as a patent foramen ovale, or other abnormalities with right-to-left shunting.3

Cardiopulmonary exercise testing (CPET) is valuable in assessing the mechanisms behind exercise intolerance, especially in patients with multiple comorbidities.18 The typical pattern observed in PH patients includes low end-tidal partial pressure of carbon dioxide (PETCO2), high ventilatory equivalent for carbon dioxide (VE/VCO2), low oxygen pulse (VO2/heart rate), and low peak oxygen uptake (VO2).29 Normal peak VO2 indicates a low likelihood of PAH in populations at risk, such as SSc patients.30

Computed tomography pulmonary angiography (CTPA) is a valuable exam for assessing these patients, providing information on the lung parenchyma and vascular dilation, detecting signs of PVOD, and excluding thrombotic phenomena or major congenital heart defects.

Once the diagnosis of PH is strongly suspected, patients should be referred to PH reference centers for optimal management.

The third step, confirmation, relies solely on right heart catheterization (RHC). This invasive test is the gold standard method to confirm the diagnosis of PH and provides a comprehensive assessment of pulmonary hemodynamics.31 The results of this procedure can vary widely depending on operator experience and patient volume status.32

Routinely measured hemodynamic parameters are presented in Table 4.

As previously stated, PH is defined by mPAP >20 mmHg. A precapillary PH phenotype is defined by mPAP >20 mmHg, PAWP ≤15 mmHg, and PVR >2 WU. In patients with borderline PAWP, fluid bolus or exercise hemodynamics may reveal ventricular diastolic dysfunction and a postcapillary component.

The concept of ‘exercise PH’ has been redefined as an mPAP/CO slope >3.0 mmHg/L/min, bearing in mind that the previous definition of mPAP >30 mmHg during exercise (abandoned in 2008) included a significant number of healthy athletes with high CO that was not necessarily pathologic.3

Another indicator recommended for distinguishing between pre- and postcapillary PH at exercise is a PAWP/CO slope with a threshold of >2 mmHg/L/min. This may be particularly important in cases of borderline PAWP between 13 and 15 mmHg, which poses a diagnostic challenge between PAH and PH associated with left heart disease. When PAWP falls within this range, it suggests the possibility of a mixed or indeterminate etiology of PH, in which both pre- and postcapillary factors may contribute to elevated pulmonary pressure. In such cases, additional assessments, including clinical history, physical examination, imaging studies, and hemodynamic response to exercise or other interventions, are necessary to determine the underlying pathology and guide treatment decisions.

Despite its widespread acceptance, further standardization of RHC is necessary to ensure its optimal use in routine clinical practice. To ensure accurate assessment of directly measured or calculated hemodynamic parameters, attention should be directed toward standardizing procedures, such as the position of the pressure transducer and the volume of catheter balloon inflation. Measurement of PAWP is susceptible to over- or under-wedging, potentially leading to false readings. Consequently, errors in RHC measurement and data interpretation can complicate differentiation of PAH from other PH disorders, resulting in misdiagnosis. Beyond diagnosis, the role of RHC, in conjunction with noninvasive tests, is rapidly expanding to include monitoring treatment response and establishing the prognosis of patients diagnosed with PAH.

The fourth step, classification, is of the utmost importance to properly identify the underlying cause of PH and to direct therapy.

An extensive clinical history is crucial and should cover all the clinical subgroups (Table 5).

Laboratory testing is mandatory18 and should assess concomitant organ damage and comorbidities (blood counts, electrolytes, kidney and liver function markers, iron status, thyroid function, and N-terminal pro-brain-type natriuretic peptide [NT-proBNP]). Directed etiologic studies such as HIV and hepatitis serology will enable identification of possible subgroups, and an autoimmune panel should be obtained.18 In patients originating from or having traveled to schistosomiasis endemic areas, microscopic urine and stool examination should be requested and/or serologic tests performed.

An abdominal ultrasound with portal vein Doppler interrogation is recommended, particularly if liver disease is suspected in patients with newly diagnosed PH, to detect liver disease, portal hypertension or portocaval shunts.18

Ventilation–perfusion lung scanning is key to rule out a diagnosis of CTEPH, the main differential diagnosis in precapillary PH, with superior results compared to CTPA performed outside PH expert centers.18

Genetic counseling is taking on an increasingly important role in managing PAH patients, as mutations in PAH genes have been identified in familial PAH, idiopathic PAH (IPAH), anorexigen-associated PAH and PVOD. Patients should be informed about the possibility of a hereditary component, and counseling should be provided by trained professionals.3

Risk stratification is essential in managing PAH patients, enabling assessment of disease severity, determination of an appropriate treatment strategy, and guidance of therapeutic adjustments. Risk assessment uses multiparametric scores gathering information from symptoms, exercise capacity and RV function.33

Several scores are currently available, notably COMPERA 2.0,34 the ESC/ERS risk assessment tool28 (Table 6), and the REVEAL 2.0 risk score.35 Different risk scores may have unique strengths and limitations, and the choice of risk assessment tool may vary based on clinician preference and institutional practice.

Currently approved therapies can be divided into three major categories according to their therapeutic target: prostacyclins (cyclic adenosine monophosphate [cAMP] pathway), phosphodiesterase (PDE)-5 inhibitors and soluble guanylate cyclase stimulators (nitric oxide [NO]-cyclic guanosine monophosphate [cGMP] pathway), and endothelin receptor antagonists (ERAs) (endothelin-1 [ET-1] pathway). In addition, CCBs can be utilized in a specific subset of patients (Figure 1).

These therapies rely on the premise of vasodilation and have been the mainstay approach in recent decades. Their use has significantly improved quality of life, functional status, and survival.18 They do not, however, address the fundamental processes that initiate and perpetuate the disease, and have little effect on fibrotic and proliferative changes, and so have no curative potential.

Treatment strategies have evolved in parallel with advances in the development of novel agents. Current guidelines18 recommend adapting the initial strategy according to disease etiology, comorbidities, and risk assessment. In addition to targeted drug therapy, which will be discussed below, general measures can be applied to all patients, regardless of subtype (Table 8 and Figure 7).

Figure 7.

Pulmonary arterial hypertension treatment algorithm.

a Cardiopulmonary comorbidities are conditions associated with an increased risk of left ventricular diastolic dysfunction, and include obesity, hypertension, diabetes, and coronary heart disease; pulmonary comorbidities may include signs of mild parenchymal lung disease and are often associated with a low DLCO.

b Intravenous epoprostenol or intravenous/subcutaneous treprostinil.

DLCO: diffusion capacity of the lung for carbon monoxide; ERA: endothelin receptor antagonist; PCA: prostacyclin analog; PDE-5i: phosphodiesterase 5 inhibitor; PRA: prostacyclin receptor agonist; sGCs: soluble guanylate cyclase stimulator.

Adapted from the 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension.1

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Preventing situations that could lead to right heart decompensation is paramount. It is recommended that patients with PAH receive vaccinations against Streptococcus pneumoniae, influenza, and the SARS-CoV-2 virus.18

Optimization of volume status with diuretics is important in patients with RV dysfunction to reduce symptoms of overload and improve hemodynamics.77 Particular attention is recommended to correction of anemia and iron deficiency. Supplementary oxygen should be provided to patients with respiratory insufficiency. Exercise training programs should be encouraged in patients who can tolerate them and adapted to patients with worse functional capacity. Psychosocial support should be made available, and patients should be provided with information regarding prognosis, if they so desire. Choices regarding treatment decisions should be shared with properly informed patients, as with all decisions in modern practice.

For vasodilator responders, initial therapy with high-dose CCBs should be initiated. These patients are to be closely monitored, with a complete reassessment after 3–6 months of therapy, including RHC. Additional acute vasoreactivity testing should be performed at reassessment to confirm sustained vasodilator response.1 Patients deemed to have a satisfactory chronic response are those who present with WHO-FC I/II and hemodynamic improvement (ideally, mPAP <30 mmHg and PVR <4 WU). In the absence of a satisfactory response, additional PAH therapy should be instituted (Figure 7).

Most clinical trials study populations with idiopathic, heritable, drug or connective tissue disease-associated PAH. This section will discuss therapeutic management of these patients (Figure 7).

Combination therapies have been progressively adopted as an early option in the treatment of PAH as they enable multiple signaling pathways to be targeted. Meta-analyses have shown reductions in time to clinical worsening and improvements in clinical outcomes when sequential combination therapy was added following suboptimal response to monotherapy,78 and benefits of combination therapy over monotherapy.79

Regarding initial strategy, AMBITION80 was a pivotal trial in combination therapy, comparing initial dual therapy with ambrisentan and tadalafil versus monotherapy with either ambrisentan or tadalafil, in treatment-naïve patients. In a follow-up of 73 weeks, a 50% risk reduction was recorded with initial dual therapy, for the primary endpoint of time to clinical event (composite of death, hospitalization for worsening PAH, disease progression, or unsatisfactory long-term clinical response). There were also significant improvements in 6MWD and NT-proBNP with initial combination therapy.

Bearing in mind the pathophysiology of PAH, initial triple therapy would logically result in even better outcomes. However, this was not the case in the TRITON study,81 which compared initial triple-combination therapy with macitentan, tadalafil and selexipag to initial dual therapy with macitentan and tadalafil in treatment-naïve patients. There were no significant differences between the groups regarding PVR (reductions of 54% and 52% respectively), 6MWD (increases of 56 m and 55 m) and mean NT-proBNP. This trial did not show benefit in initial triple therapy but did reinforce evidence supporting initial ERA/PDE-5i combination therapy.

Data from the French registry,82 however, showed that initial triple-combination therapy including an IV/SC prostacyclin analog was associated with better long-term survival than monotherapy or dual combination therapy. More studies are required to clarify whether initial triple therapy is a superior approach, and in which patients it should be initiated.

The current guidelines18 stratify patients according to risk (see section “Risk assessment”) and the presence or absence of cardiovascular comorbidities associated with an increased risk of LV diastolic dysfunction (such as obesity, hypertension, diabetes, or ischemic heart disease) or pulmonary comorbidities, to guide therapy. In a population as complex as PH patients, however, treatment decisions must be personalized, going beyond simplified algorithms.

As research advances, the focus has been on acting upstream in the pathophysiological chain, with the objective of not only halting disease progression earlier, but also attempting to reverse tissue damage and remodeling.

Genetic pathways are known to play a critical role in the pathogenesis of PAH. Mutations in BMPR2 have been identified as the most frequent cause of heritable PAH.4 This pathway is also involved in the development of PAH in patients without heritable disease.86

Sotatercept is a first-in-class fusion protein that acts as a ligand trap for members of the TGF-β superfamily, thus restoring balance between the growth-promoting activin growth differentiation factor pathway and the growth-inhibiting bone morphogenetic protein (BMP) pathway. In PULSAR, a randomized, double-blind, placebo-controlled phase 2 trial, subcutaneous administration of sotatercept met the primary endpoint assessed at week 24, with a significant reduction of 34% in PVR compared to placebo, in addition to approved background therapy.87 Efficacy for secondary endpoints including 6MWD, NT-proBNP, RAP and mPAP was also shown. The phase 3 multicenter double-blind STELLAR trial88 that included 323 patients with PAH on background therapy showed a significant change in the primary endpoint (exercise capacity as assessed by 6MWD) and eight out of nine secondary endpoints. The main adverse events were thrombocytopenia, increase in hemoglobin and telangiectasia (in about 10% of patients).

KER-012 is a novel molecule, designed to bind to and inhibit the signaling of TGF-β ligands, including activin A, activin B and myostatin, potentially increasing the signaling of BMP pathways. TROPOS, a randomized, double-blind, placebo-controlled phase 2 clinical trial, is currently underway to evaluate KER-012 in combination with background therapy in patients with PAH. Outcomes will include changes in PVR, 6MWD, and safety parameters.

The platelet-derived growth factor-mediated pathway, which promotes the proliferation of PASMCs and an inflammatory environment, has also been identified as a therapeutic target.89

Imatinib, a tyrosine kinase inhibitor currently used to treat multiple cancers, was the first antiproliferative to have demonstrated clinical efficacy in phase 2 and 3 trials of PAH when administered orally. However, systemic side effects limited its therapeutic use.90 The IMPAHCT study, a currently ongoing phase 2B/3 trial, will evaluate the safety, tolerability, and clinical benefit of inhaled imatinib in PAH.

Seralutinib, another tyrosine kinase inhibitor, acts through the same mechanism, and has been evaluated in the TORREY phase 2 study, in which it led to a reduction of 14% in PVR and significant reductions in NT-proBNP levels and improvement in 6MWD and functional class.91

There are a myriad other therapeutic targets and ongoing clinical studies, with targets ranging from hormonal pathways (e.g. anastrozole and tamoxifen) to metabolism (bardoxolone, metformin and ranolazine), epigenetic alterations and DNA damage (apabetalone and histone deacetylase inhibitors), the serotonin pathway (serotonin reuptake inhibitors), and vasoactive agents (apelin receptor agonists).

PAH is a complex disease, a consequence of vascular dysfunction and remodeling, that stems from multiple possible etiologies. Patients should be managed at high-volume and experienced centers. Nonetheless, diagnosis results from clinical suspicion, and physician awareness is key.

The field of PAH management is ever-changing, and current research brings the promise of increasingly effective and safe options for this high-risk group of patients with a historically poor prognosis.

The authors have no conflicts of interest to declare.