Pulmonary arterial hypertension (PAH) is a severe and progressive disease that can occur without an identifiable cause or can be associated with an underlying condition.
On this page, you will find information on the clinical classification of PAH, key patient demographics, pathophysiology and typical symptoms.
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PAH is a rare and severe disease characterised by progressive narrowing of the pulmonary arteries. If left untreated, it eventually results in right heart failure and death.
Pulmonary hypertension (PH) refers to elevated blood pressure in the pulmonary arteries and can be caused by various pulmonary and cardiac pathologies that increase pulmonary arterial pressure (PAP). PAH describes a subgroup of patients with PH characterised by the presence of pre-capillary PH, defined as mean PAP >20 mmHg, mean pulmonary arterial wedge pressure ≤15 mmHg and pulmonary vascular resistance (PVR) >2 Woods units, in the absence of other causes of PH.
Adapted from Humbert et al. 2022
The 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines categorise PH into 5 main groups, with PAH being the first group.
Adapted from Humbert et al. 2022
Idiopathic PAH (IPAH)
IPAH is the most common form of PAH, accounting for approximately 50–60% of cases in Europe and the USA. It occurs sporadically without a family history or other identifiable risk factors.
Heritable PAH (HPAH)
HPAH accounts for approximately 6% of PAH cases and includes patients with a family history of PAH and those carrying a mutation in a gene known to be associated with PAH.
Drug and toxin-induced PAH
PAH can be associated with exposure to certain drugs or toxins, particularly appetite suppressants, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and many have been withdrawn from the market. Since then, additional new drugs have been identified or suspected as potential risk factors for PAH, including bosutinib, sofosbuvir and leflunomide.
Many patients with PAH have an associated disease, such as connective tissue disease, congenital heart disease, portal hypertension, HIV infection or schistosomiasis. These are discussed in the next section.
Types of diseases associated with PAH include connective tissue disease (CTD), congenital heart disease (CHD), portal hypertension, HIV infection and schistosomiasis.
Adapted from Humbert et al. 2022 and Lau et al. 2017
PAH associated with connective tissue disease (CTD-PAH)
CTD-PAH is the most common subtype of PAH associated with another disease, comprising approximately 15–30% of cases. PAH is most commonly seen in systemic sclerosis (SSc), which accounts for almost 75% of CTD-PAH cases. Approximately 10% of patients with SSc develop PAH. The remaining cases of CTD-PAH are due to systemic lupus erythematosus (8–19%), mixed CTD (8–9%), rheumatoid arthritis (3–5%), dermatomyositis/polymyositis (4%), undifferentiated CTD (2%) and Sjögren's syndrome (1%).
PAH associated with congenital heart disease (CHD-PAH)
CHD-PAH accounts for 10–23% of PAH cases. The 2022 ESC/ERS guidelines provide a clinical classification for CHD-PAH:
1. Eisenmenger syndrome
2. PAH associated with prevalent systemic-to-pulmonary shunts
3. PAH with small/coincidental defects
4. PAH after defect correction
PAH associated with HIV infection (HIV-PAH)
PAH is a rare complication of HIV infection. The use of antiretroviral therapy has increased the life expectancy of HIV patients. In addition, the incidence of HIV-PAH has declined in parallel with the increased availability of antiretroviral therapy. Together, these effects have resulted in an overall stable HIV-PAH prevalence of 0.5%.
PAH associated with portal hypertension (PoPH)
PoPH accounts for approximately 5–15% of cases, and can develop in the presence or absence of liver disease. PoPH develops in an estimated 1–2% of patients with liver disease and portal hypertension.
PAH associated with schistosomiasis (Sch-PAH)
Schistosomiasis is a parasitic disease caused by trematode flatworms called schistosomes, and is highly prevalent across South America, Asia and Africa. Globally, around 10–20% of patients with schistosomiasis and hepatosplenic disease develop PAH.
PAH is a rare disease, with an estimated prevalence of 48–55 cases per million and an incidence of ~6 cases per million.
PAH can occur at any age, but is frequently diagnosed in older patients (i.e. those aged >65 years). There is also a greater incidence of PAH in female patients vs male patients, with registries reporting on average 70–80% female patients with PAH.
Adapted from NHS Digital 2022
Patients with PAH have a poor prognosis. The course of PAH is variable and the rate at which disease progression occurs depends on several factors, such as the underlying aetiology of the patient's disease.
As shown in the 2020–2021 National Audit of Pulmonary Hypertension, the prognosis of PAH varies according to PAH subtype.
Adapted from NHS Digital 2022
Patients with SSc-PAH have a particularly poor prognosis compared with other forms of PAH, with PAH being one of the leading causes of death in patients with SSc-PAH.
Patients with CHD-PAH represent a varied patient population whose clinical presentation may differ. Despite being the most advanced form of CHD-PAH, with the most severe exercise intolerance, patients with Eisenmenger syndrome have better survival rates compared to the other CHD-PAH subgroups. On the other hand, patients with CHD who develop PAH following defect correction have the worst outcomes.
The prognosis of PAH associated with HIV is worse than for HIV infection alone or for IPAH. Treatment with highly active antiretroviral therapy correlates with a reduction in incidence of HIV-PAH, indirectly supporting the efficacy of antiretroviral therapies for the treatment or prevention of PAH.
Compared with IPAH, patients with PoPH have worse survival rates. The long-term prognosis in PoPH is related to the severity of cirrhosis and cardiac function.
Though the exact causes behind the development of PAH remain unknown, research has led to a better understanding of the underlying pathophysiology. PAH is a complex, multifactorial condition involving numerous biochemical pathways and different cell types.
Narrowing of the pulmonary arteries occurs in PAH as a result of vascular remodelling, which involves changes to all three layers of the vessel wall via multiple pathological mechanisms. Vascular remodelling leads to chronic elevation of PVR and PAP. This, in turn, leads to increased afterload on the right ventricle, eventually progressing to right heart failure.
Healthy pulmonary artery
Adapted from Galiè et al. 2010
Pulmonary artery in PAH
Vascular remodelling in PAH is a result of multiple pathological mechanisms occurring at each layer of the pulmonary artery wall:
• Intima: Endothelial-mediated vasoconstriction, cell proliferation, fibrosis
• Media: Hypertrophy, smooth muscle cell hyperplasia, vasoconstriction
• Adventitia: Increased inflammation, fibrosis-induced vascular stiffening
The prominent pathological features of PAH include:
• Intimal proliferation and medial hypertrophy
• Remodelling/fibrosis of the adventitia
• Development of plexiform lesions at arterial branch points
Adapted from Gaine et al. 2000
The increase in PAP (afterload) strains the right side of the heart. Initially, the right ventricle can compensate for the increased afterload by undergoing remodelling, including increased contractility, hypertrophy and dilatation. As PAH progresses, however, the heart can no longer compensate and becomes uncoupled from its load.
Adapted from Vonk Noordegraaf et al. 2013
Find out about the different screening strategies used in at-risk patients. Patients with suspected PAH should be referred to a specialist centre for further investigation.
Explore and investigate the options to diagnose PAH.
CHD, congenital heart disease; CTD, connective tissue disease; Ea, arterial elastance; Ees, end-systolic elastance; ERS, European Respiratory Society; ESC, European Society of Cardiology; HIV, human immunodeficiency virus; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; PAP, pulmonary arterial pressure; PCH, pulmonary capillary haemangiomatosis; PH, pulmonary hypertension; PoPH, portopulmonary hypertension; PVOD, pulmonary veno-occlusive disease; PVR, pulmonary vascular resistance; RV, right ventricular; SMC, smooth muscle cell; Sch, schistosomiasis; SSc, systemic sclerosis