From the Guidelines
Group 1 Pulmonary Arterial Hypertension (PAH) is caused by several distinct conditions, including idiopathic PAH, heritable PAH, drug and toxin-induced PAH, and PAH associated with other conditions such as connective tissue diseases, HIV infection, portal hypertension, congenital heart diseases, and schistosomiasis, as outlined in the 2015 ESC/ERS guidelines 1. The main causes of Group 1 PAH can be broken down into:
- Idiopathic PAH (with no identifiable cause)
- Heritable PAH (genetic mutations, particularly in the BMPR2 gene)
- Drug and toxin-induced PAH (associated with medications like appetite suppressants and illicit drugs)
- PAH associated with other conditions, including:
- Connective tissue diseases (particularly systemic sclerosis, lupus, and mixed connective tissue disease)
- HIV infection
- Portal hypertension
- Congenital heart diseases (especially those with systemic-to-pulmonary shunts)
- Schistosomiasis These conditions lead to vascular remodeling, vasoconstriction, and in-situ thrombosis of pulmonary arteries, resulting in increased pulmonary vascular resistance, right ventricular strain, and eventually right heart failure if left untreated, as described in the 2022 ACR Appropriateness Criteria 1. The most recent and highest quality study, the 2015 ESC/ERS guidelines 1, provides a comprehensive classification of pulmonary hypertension, including Group 1 PAH, and highlights the importance of identifying the underlying cause of PAH to guide treatment and management. Additionally, the 2019 European Respiratory Review article 1 emphasizes the importance of registries in understanding the epidemiology and outcomes of PAH, and the 2009 ACCF/AHA expert consensus document 1 provides further insight into the classification and epidemiology of PAH. However, the 2015 ESC/ERS guidelines 1 remain the most recent and highest quality study, providing the most up-to-date information on the causes of Group 1 PAH. The underlying pathophysiology of PAH involves vascular changes characterized by endothelial dysfunction, smooth muscle cell proliferation, inflammation, and fibrosis, resulting in narrowing of the pulmonary arterial lumen and increased pulmonary arterial pressure, as discussed in the 2015 ESC/ERS guidelines 1 and the 2022 ACR Appropriateness Criteria 1. Overall, the causes of Group 1 PAH are complex and multifactorial, and accurate diagnosis and treatment require a comprehensive understanding of the underlying conditions and pathophysiology, as outlined in the 2015 ESC/ERS guidelines 1.
From the Research
Causes of Group 1 PAH
The causes of group 1 Pulmonary Arterial Hypertension (PAH) are complex and multifactorial. Some of the key causes include:
- Genetic mutations, particularly in the gene encoding bone morphogenetic protein receptor 2 (BMPR2) 2, 3, 4, 5, 6
- Cytoskeletal defects, which have been shown to be associated with BMPR2 mutations 3
- Abnormalities in the transforming growth factor beta superfamily, which interacts with the BMPR2 receptor 2
- Other genetic mutations, such as those in the ACVRL1 and KCNA5 genes, which have been identified in some patients with PAH 6
Genetic Mutations
Genetic mutations, particularly in the BMPR2 gene, are a major cause of group 1 PAH. Studies have shown that:
- More than 50% of cases of familial PAH are associated with mutations in the BMPR2 gene 2
- BMPR2 mutation carriers are younger at diagnosis, have higher mean pulmonary artery pressure, and lower cardiac index compared to non-carriers 4
- Pathogenic mutations in the BMPR2 gene are frequent in patients with idiopathic and associated PAH group I, and are associated with increased disease severity 6
Other Causes
Other causes of group 1 PAH include:
- Idiopathic PAH, which is PAH without a known cause 2, 4
- Associated PAH, which is PAH associated with other conditions, such as connective tissue disease or congenital heart disease 4, 6
- Environmental and lifestyle factors, which may contribute to the development of PAH, although the exact mechanisms are not fully understood 5