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.
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 ≥25 mmHg, mean pulmonary arterial wedge pressure (PAWP) ≤15 mmHg and pulmonary vascular resistance (PVR) >3 Woods units, in the absence of other causes of PH.
Adapted from Galiè et al. 2016
Idiopathic PAH (IPAH)
IPAH is the most common form of PAH, accounting for approximately 30–50% of cases. 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 These drugs have been confirmed to be risk factors for PAH and many have been withdrawn from the market. Over the last 5 years, new drugs have been identified or suspected as potential risk factors for PAH, including bosutinib, sofosbuvir and leflunomide.
Approximately half of 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 Galiè et al. 2016 and National Audit of Pulmonary Hypertension 2018-2019
PAH associated with connective tissue disease (CTD-PAH)
CTD-PAH is a common subtype of PAH, comprising approximately 22–31% of cases. PAH is most commonly seen in scleroderma, which accounts for almost 75% of CTD-PAH cases. Approximately 10% of patients with scleroderma 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 Sj.gren's syndrome (1%).
PAH associated with congenital heart disease (CHD-PAH)
CHD-PAH accounts for 13–36% of PAH cases and represents a heterogeneous patient population. The 2015 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. While the use of antiretroviral therapy has increased the life expectancy of HIV patients, it has also decreased the incidence of HIV-PAH, resulting in an overall stable HIV-PAH prevalence of 0.5%.
PAH associated with portal hypertension (PoPH)
PoPH accounts for approximately 5% of cases, and can develop in the presence or absence of liver disease. However, as cirrhotic liver disease is the most common cause of portal hypertension, PoPH is most frequently encountered in patients with cirrhosis.
PAH associated with schistosomiasis (SCH-PAH)
Schistosomiasis is a parasitic disease caused by trematode flatworms called schistosomes, and is highly prevalent across 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 15–60 cases per million and an annual incidence of 5–10 cases per million in Europe.
PAH can occur at any age, but the mean age at diagnosis observed in registries is between 50 and 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 National Audit of Pulmonary Hypertension 2018–2019
Without treatment, 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 2018 Great Britain National Audit of Pulmonary Hypertension, the prognosis of PAH varies according to PAH subtype.
Adapted from National Audit of Pulmonary Hypertension 2018–2019
Patients with scleroderma-associated 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 scleroderma-associate PAH.
Patients with CHD-PAH represent a varied patient population whose clinical presentation may differ. Despite being the most severe form of CHD-PAH, patients with Eisenmenger syndrome have better survival 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 significantly improves survival in these patients, including deaths directly attributable to PAH, as well as other causes.
Compared with IPAH, patients with PoPH have worse survival. 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 and medial hypertrophy
• Remodelling/fibrosis of the adventicia
• Development of plexiform lesions at arterial branch points
Adapted from Gaine et al. 2000
The increase in pulmonary arterial pressure (afterload) strains the right 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; HIV, human immunodeficiency virus; HPAH, heritable pulmonary arterial hypertension; IPAH, idiopathic pulmonary arterial hypertension; PAH, pulmonary arterial hypertension; PAP, pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PH, pulmonary hypertension; PoPH, portopulmonary hypertension; PVR, pulmonary vascular resistance; RV, right ventricular; SMC, smooth muscle cell