The Pathophysiology, Mechanism, Diagnosis, and Management of Pulmonary Arterial Hypertension: A Comprehensive Literature Review

Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (mPAP) greater than 20 mmHg on resting right heart catheterization (RHC) and encompasses a group of cardiovascular-pulmonary diseases with distinct etiologies and a wide spectrum of clinical implications.^1,2 PH is clinically classified into five WHO groups based on RHC hemodynamics, etiologies, clinical presentation, physiopathology, and treatment response.^1,3

The first scientific postmortem anatomic description suggestive of PH dates back to the late 19th century by Von Romberg.⁴ Advances in the pathological and hemodynamic understanding of cardiopulmonary vasculature interactions emerged in the decades following the RHC development, first performed by Werner Forssmann on himself in 1929.⁵ The technique underwent significant refinement in the second half of the 20th century.^4–10 In the 1960s in Switzerland, there was a significant increase in the diagnosis of primary PH, which was attributed to the medication aminorex, a known appetite suppressant for weight loss. This association raised awareness of the disease, leading to the drug’s withdrawal from the market.¹¹ The association between the disease and the drug was further strengthened after a significant reduction in the disease prevalence was observed once the drug was recalled, establishing the first consistent documented link between PH and drugs.⁶

The variability in the disease’s severity and nomenclature led to the first world scientific meeting (World Symposium on Pulmonary Hypertension [WSPH]), which was dedicated to unifying and summarizing the definition of PH. The meeting first took place in 1973, and the latest iteration was in 2024.¹² Currently, PH is clinically classified into five WHO groups based on RHC hemodynamics, etiologies, clinical presentation, physiopathology, and treatment response. In this brief review we will focus on the key clinical aspects of pulmonary arterial hypertension (PAH), also known as PH WHO Group I.¹³

PAH has multiple etiologies that ultimately cause progressive pulmonary arterial vascular remodeling with lumen narrowing and subsequent right heart failure with a high mortality rate if left untreated.^1,14 Commonly, the disease presents with progressive shortness of breath and exercise intolerance, further explored later in this review. The estimated PAH prevalence is 5 to 52 per million. However, this is likely to be underestimated due to limited disease recognition, delayed diagnosis, and differences in diagnosis across different registries.^1,15,16 PAH can affect all ages and sexes, with a predominance in young women, and a recent increase in diagnosis of the disease, often of mixed etiology, in patients 55 years of age and older.^14,17,18 Due to the increasing age at diagnosis and the decreasing female sex preponderance, the number of cardiopulmonary comorbidities in PAH patients is rising. This can cause difficulty in accurate diagnosis and predispose to adverse effects with PAH-specific treatment. PAH is subcategorized based on the predominant pathological mechanisms, underlying disease, and the treatment response (Table 1).^1,12

Pathophysiology

PAH pathophysiological mechanisms are complex and variable depending on the underlying etiology; the mechanisms have not been entirely elucidated. One prevailing concept is that the pulmonary vasculature depends on a finely regulated balance between proliferative and antiproliferative forces, as well as vasoconstrictive and vasodilatory mechanisms. A shift favoring excessive cellular proliferation is a key pathophysiological process leading to PAH (Figure 1).¹⁶ The vascular remodeling tends to affect all three layers of the vessels (intima, media, and adventitia), predominantly, and typically it affects the distal pulmonary vasculature.^10,19

Although the pathophysiological mechanisms may differ depending on the underlying disease, it is characterized by endothelial proliferation (intima thickening), intimal fibrosis, plexiform formation (endothelial cell monoclonal overgrowth), smooth-muscle cell hyperplasia (medial hypertrophy), fibroblast proliferation, inflammatory cells infiltration, and collagen disruption (adventitia), ultimately leading to substantial luminal narrowing and increase in pulmonary vascular resistance (PVR).^19,20 These remodeling processes primarily affect pre-capillary vessels (50–500 μm) and, to some extent, similar post-capillary changes may happen, explaining the findings on PAH with overt features of venous or capillary involvement (pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis).²¹ Consequently, all of these changes lead to a state of vasoconstriction, inflammation, shear stress, and uncontrolled vessel cell growth, perpetuating a pathological vicious cycle.²²

Endothelial Dysfunction

PAH therapies target the endothelial dysfunction aspect mainly by aiming to reduce vasoconstriction, promote vasodilation, and inhibit endothelial proliferation. Three important pathways are involved in these mechanisms: the endothelin 1 (ET₁), nitric oxide (NO), and prostacyclin (PGI₂) pathways (Table 2).^19,22,23 In PAH there is a pathological increase in ET_1, which acts on two endothelin receptor subtypes, ET_A and ET_B, located on pulmonary smooth muscle and vascular endothelium, with a pulmonary vascular net effect of vasoconstriction and cellular proliferation.^12,23,24 ET_A stimulation leads to pulmonary vascular vasoconstriction (vascular smooth muscle cells) and proliferation, while ET_B (vascular endothelial and smooth muscle cells) causes vasodilation, antiproliferation, and endothelium clearance. Ambrisentan, an endothelin receptor antagonist (ERA) medication, has a much greater inhibitory affinity for ET_A than ET_B and is at the point of being considered a selective ET_A receptor antagonist.²⁴ Bosentan and macitentan are both ERAs that inhibit ET_A and ET_B with a more balanced inhibitory affinity between these two ET₁ receptors.^12,24 Further details on their differences in clinical practice are discussed in the treatment section below. The PGI₂ and NO pathways ultimately lead to vasodilation and antiproliferation by the increase of the second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), respectively.²⁵ The PGI₂ and NO pathways are both decreased in PAH, and thus, an important part of the current therapeutic options involves increasing cAMP and cGMP availability through different strategies.²⁶ The increase in cAMP can be achieved by PGI₂ analogs (epoprostenol, treprostinil, iloprost) or prostacyclin receptor agonists (selexipag).¹ cGMP can be increased directly by riociguat (independently from the NO pathway) or by phosphodiesterase-5 (PDE5) inhibitors (sildenafil and tadalafil), which decreases the rate of cGMP conversion into its vasodilatory inactive form guanosine monophosphate (GMP; Table 2).^26,27

Genes and Protein Signaling

As previously mentioned, the intracellular signaling and gene expression to maintain the homeostatic balance between proliferative and antiproliferative endothelial cells is complex, involving many genes and related signal proteins (Table 3).¹² Many of these mechanisms are not entirely understood, but the interest in this complex pathophysiology has significantly grown as possible therapeutic targets. Notably, 12 genes have now been classified as having definitive evidence for causality in PAH, with an additional six genes showing moderate evidence, underscoring the strong genetic basis of this disease.²⁸ Dysregulated overexpression of specific TGF-β pathway components contributes to endothelial dysfunction and a shift toward pro-proliferative signaling in PAH.^29–32 Noticeably, the activin receptor type IIA (ActRIIA) is involved in the anti-apoptotic pathological behavior of endothelial cells.³⁰ Sotatercept is a new fusion protein that works as a trap ligand of ActRIIA, and Phase II and Phase III randomized clinical trials have shown clinical benefits in patients with PAH.^33,34 Further understanding of these complex signaling pathways in PAH is promising for potential new therapeutic advancements.^31,32

Clinical Features and Diagnostic Evaluation

There is a wide array of clinical features and symptoms that can develop in patients with PAH. These clinical features are often non-specific to the disease process, which has led to significant delays in diagnosis and management, and contributing to poor prognosis and outcomes. The common symptoms can vary from shortness of breath on exertion and in more severe forms at rest, from non-specific chest pains to classic angina, fatigue and lightheadedness, to presyncope and frank syncope in severe cases with marked right ventricle dysfunction.

History of Present Illness and Focused Physical Exam

One important step to avoid delays in diagnosis is to obtain a thorough personal and family history, including current medications (prescribed and over-the-counter), inherited conditions, toxin exposures, recreational drug use, and occupational hazards. Supporting physical examination findings suggestive of elevated pulmonary pressures include an accentuated P2 heart sound, a tricuspid regurgitation (TR) murmur, jugular venous distention, and a right ventricular (RV) heave or thrill. In later stages of the disease, signs and symptoms of RV failure may be present, such as increased abdominal girth, a positive fluid wave, hepatojugular reflux (HJR), and peripheral edema. A retrospective analysis was conducted using the ESCAPE trial dataset to evaluate the clinical importance of HJR. It was found that there is a strong correlation between the presence of HJR and elevated right-sided filling pressures and pulmonary artery pressures.³⁵

Echocardiographic Diagnosis

The current standard and the most cost-effective screening non-invasive test for the diagnosis of PH is a transthoracic echocardiogram (TTE). TTE has also proven to be a useful tool in identifying potential causes and etiologies of PH. On TTE, the pulmonary arterial systolic pressure (PASP) can be indirectly estimated by different methods, using a systolic pressure of 35 mmHg or an mPAP cut-off of 20 mmHg to define PH. PASP can be estimated, first, with spectral continuous wave (CW) Doppler assessment of TR peak velocity and gradient using the modified Bernoulli’s equation (4V²) and adding the estimated right atrial pressure (RAP), using a given estimate based on the inferior vena cava (IVC) diameter and collapsibility (IVC < 2 cm and <50% collapsibility = RAP 5 mmHg; IVC >2 cm and >50% collapsibility = RAP 10 mmHg; IVC >2 cm and <50% collapsibility = RAP 15 mmHg; IVC >2 cm and no collapsibility = RAP 20 mmHg).³⁶ This method can be inaccurate in the presence of AF, primary tricuspid valve pathology with significant valvular regurgitation, or chronic RV failure. Second, PASP can be indirectly assessed using RV outflow tract acceleration time (AT) measured with pulsed-wave Doppler below the pulmonary valve, because shorter AT values correlate with higher pulmonary artery pressures. Lastly, in the presence of pulmonary regurgitation, the regurgitant jet can be used to estimate mean pulmonary artery pressure (mPAP) by placing a continuous-wave Doppler beam through the pulmonary valve to measure the early-diastolic pulmonary regurgitation velocity; the pressure gradient is calculated with the modified Bernoulli equation and added to the estimated RAP. This method can be inaccurate in the presence of constrictive/restrictive physiology.³⁷ Of these methods, assessment of the peak TR velocity remains the preferred variable for determining the pre-test probability of PH.

Additional echocardiographic features can provide insight into various etiologies for PH. For example, in cases of left ventricular (LV) systolic or diastolic dysfunction, elevated LV and left atrial pressures and chamber enlargement may be visualized on TTE, suggestive of Group 2 PH. TTE can also help assess other causes of Group 2 PH, including valvular heart disease and infiltrative or restrictive cardiomyopathies. In contrast, echocardiographic findings such as pericardial effusion are more commonly associated with PAH and serve as markers of poor prognosis. While the presence of PH can be suggested by TTE, the gold standard for diagnosis is RHC. The decision to pursue invasive hemodynamic testing should be determined by the pre-test probability of precapillary disease, given that this etiology needs to be confirmed in a timely fashion to avoid treatment delay.

Invasive Hemodynamic Assessment and Diagnosis

Complete hemodynamics through an RHC should be performed to confirm the diagnosis of PH and classify the type of PH based on hemodynamics and WHO groups (Table 4).³⁸ An elevated pulmonary capillary wedge pressure (PCWP) usually indicates PH due to Group 2 disease. An important value is the transpulmonary gradient, which is the difference between the measured mPAP and PCWP. A transpulmonary gradient >10–12 mmHg is indicative of a pulmonary parenchyma or vasculature process such as primary interstitial lung disease, chronic obstructive pulmonary disease or asthma (Group 3), chronic thromboembolic PH (CTEPH; Group 4), or PAH (Group 1). PVR (calculated as mPAP − PCWP/cardiac output) >2 Wood units is suggestive of pulmonary vasculature pathology.³⁹ Cardiac output can be derived either by thermodilution or Fick’s equation. Both the Fick equation and thermodilution can be used but the indirect Fick method is considered less reliable than thermodilution. However, thermodilution should not be used in the presence of intracardiac shunts. PAH is further subcategorized into categories based by the etiology (Table 1).

Additional Diagnostic Studies

Following confirmation of PH by RHC, further diagnostic testing is necessary to identify the underlying WHO group and guide appropriate management. Pulmonary function tests and high-resolution CT of the chest are essential for evaluating parenchymal lung disease consistent with WHO Group 3.² Polysomnography should be performed when sleep-disordered breathing is suspected.⁴⁰ A ventilation–perfusion scan remains the preferred screening test for CTEPH (WHO Group 4).⁴¹ Laboratory studies, including antinuclear antibody and other autoantibody panels, are recommended for screening connective tissue diseases associated with Group 1 PAH.⁴² Additional testing may include HIV serology, liver imaging for portopulmonary hypertension, and genetic testing (e.g. BMPR2 and other PAH-associated genes) in selected patients with idiopathic, heritable, or early-onset PAH.^43,44 These investigations help delineate the etiology of PH and guide further therapy.

Risk Assessment

Risk stratification in PAH is critical for guiding treatment decisions and predicting clinical outcomes. Contemporary expert consensus, including the 7th WSPH, recommends using validated multiparametric risk assessment tools rather than relying solely on WHO functional class.³ These include the REVEAL 2.0 and REVEAL Lite 2 risk calculators, COMPERA 2.0, the French Pulmonary Hypertension Registry approach, and the European Society of Cardiology/European Respiratory Society (ESC/ERS) risk stratification model.^45,46 These tools integrate several key prognostic variables, most notably WHO functional class, 6-minute walk distance, and natriuretic peptide levels (brain natriuretic peptide [BNP] or NT-proBNP), along with hemodynamic and imaging parameters. Risk categories (low, intermediate, and high) correspond to estimated 1-year mortality and directly inform treatment intensification and follow-up strategies. Regular reevaluation using these tools is essential to assess treatment response and optimize long-term outcomes. In addition to risk calculators, RV imaging (particularly RV size, function, and evidence of failure) serves as an important complementary prognostic tool. Significant RV dysfunction is associated with worse outcomes and may warrant more aggressive treatment regardless of formal risk category.⁴⁷

The prognosis of PAH varies significantly based on etiology, patient demographics, and response to therapy.^48,49 Factors associated with better prognosis include female sex, younger age, and being in New York Heart Association functional class I or II at diagnosis. Conversely, systemic sclerosis-associated PAH (SSc-PAH) has a worse prognosis compared with idiopathic PAH.⁵⁰ SSc-PAH patients often present with more comorbidities and less favorable hemodynamic profiles, leading to poorer outcomes. Additionally, patients who achieve near-normal hemodynamic parameters with treatment have better long-term outcomes. The ESC/ERS and REVEAL risk scores have been shown to assess survival in prior literature.^48,49 These risk scores predict survival by incorporating clinical, biomarker, functional, and hemodynamic parameters into their model. Machine learning algorithms and predictive models using advanced imaging and statistical techniques are also emerging to enhance risk assessment. While the 2019 CHEST guidelines categorize patients into low (WHO class I), intermediate (class II/III), and high risk (class IV), more contemporary management strategies increasingly rely on comprehensive multiparametric models to guide therapeutic decisions.⁵¹

Treatment

Management is focused on PAH etiology treatment, supportive care, oxygen therapy, diuretics, vasodilatory medication and cardiopulmonary rehabilitation, and requires a multidisciplinary team. Most patients with PH will require a diuretic to prevent salt and water retention, and oxygen therapy is often necessary given that hypoxia can lead to pulmonary arterial constriction and worsening PH. While anticoagulation was previously widely recommended for PAH based on survival benefits seen in retrospective analyses, it is now considered only in the subgroup of patients with idiopathic PAH on a case-by-case basis.^45,52 The American College of Chest Physicians also emphasizes the importance of non-pharmacologic interventions in the comprehensive management of PAH.⁵¹ Cardiopulmonary rehabilitation programs can improve exercise capacity and quality of life, and palliative care should be integrated into the management plan to address symptoms and improve the quality of life, particularly in the advanced stages of the disease.

Prior to initiating PAH-specific therapy, patients should undergo vasoactive testing to identify the 10–20% of patients who will respond to calcium channel blockers (specifically in idiopathic PAH, heritable PAH, and drug/toxin-induced PAH).⁵³ If patients are vasoreactive, meeting strict criteria with dramatic improvement in mPAP, they are trialed on a high dose of calcium channel blocker therapy for 1–3 months. It is important that these patients are followed closely because few are responsive at 1 year.⁵⁴ The treatment of PAH involves targeting four primary pathways: the ET1 pathway, the NO pathway, the PGI2 pathway, and the activin signaling inhibitor pathway. Initial combination therapy with an ERA and a PDE5 inhibitor is recommended for patients at low to intermediate risk based on multiparametric risk stratification. For patients at high risk, initial triple therapy including an IV or SC prostacyclin analog is advised. Initial monotherapy is no longer recommended. This practice is guided by the AMBITION trial, which found that dual upfront therapy with ambrisentan (ERA) and tadalafil (PDE5 inhibitor) improved PAH outcomes when compared with either monotherapy.⁵⁵ Commonly used ERAs include bosentan (rarely in the US due to liver toxicity), ambrisentan, and macitentan, while PDE5 inhibitors include sildenafil and tadalafil. For patients with more severe disease at diagnosis or those who do not respond adequately at any point during their disease, prostacyclin analogs (e.g. epoprostenol, treprostinil [IV, SC, oral, inhaled]) or prostacyclin receptor agonists (e.g. selexipag) are initiated. These agents are particularly important in intermediate-high-risk patients. A recent study guiding therapy to an mPAP goal with prostacyclin demonstrated remarkable improvements in hemodynamics and RV function, suggesting perhaps a more aggressive pressure-oriented goal.⁵⁶

Sotatercept, an activin signaling inhibitor, is a new treatment for PAH. STELLAR, a Phase III study, demonstrated that adding sotatercept to single or combination therapy resulted in improved exercise tolerance, hemodynamics, quality-of-life metrics and time to clinical worsening.³³ Based on this data, the Food and Drug Administration approved the use of sotatercept in 2024 for the treatment of PAH. The ZENITH trial (NCT04896008) was a pivotal Phase III randomized controlled trial evaluating sotatercept in patients with severe PAH already on background therapy. The trial was halted early due to meeting its primary endpoint at interim analysis.⁵⁷ Sotatercept significantly reduced the time to first morbidity or mortality event compared to placebo. These findings affirm the benefit of targeting the activin signaling pathway in high-risk populations and suggest that sotatercept may be a disease-modifying therapy. Consequently, the HYPERION trial (NCT04811092), which was enrolling newly diagnosed intermediate- and high-risk patients, was also stopped early due to equipoise following the positive results of ZENITH.⁵⁸

Treatment recommendations now stress an aggressive follow-up protocol with escalation of therapy to meet low-risk status.⁵⁴ For patients who are refractory to maximal triple combination therapy, and or young and high risk, a lung transplant evaluation is necessary preferably early to assess candidacy.⁵⁹

Future Therapeutics

Several ongoing and future Phase III clinical trials are investigating new treatments for PAH. The ongoing SOTERIA trial (NCT07218029) aims to evaluate the long-term safety and sustained efficacy of sotatercept. Additionally, although halted early due to positive interim efficacy from the ZENITH trial, the HYPERION trial sought to clarify optimal patient populations and timing for sotatercept initiation.

Tyrosine kinase inhibitors (TKIs) can reduce pulmonary vascular remodeling and have been explored before in the treatment of PAH. However, medications, such as imatinib, have been shown in prior studies to have adverse effects in combination with warfarin, such as subdural hematoma.⁶⁰ Dasatanib can cause pulmonary vascular toxicity with resultant RV failure and elevated PVR.⁶¹ A novel TKI, seralutinib, completed Phase II.⁶² It is now being explored in a Phase III, randomized study, PROSERA (NCT05934526), to see its effects on exercise capacity and time to clinical worsening.

Within the well-established ET₁, NO, and PGI₂ pathways, several new medicines are undergoing early-phase clinical development.⁶³ Supplementary Table 1 lists the clinical trials in progress and summarizes the multitude of agents under evaluation. Unfortunately, PAH remains an incurable condition with limited highly specialized treatment options. However, recent advances are currently in the pipeline. As clinician scientists learn more about the pathophysiology, there is hope for more effective and safe treatments and a potential cure for PAH.

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