Greater Vessel Remodeling May Be Link Between BMPR2 Mutations and Severe PAH

Pulmonary arterial hypertension (PAH) patients who carry mutations in a gene called BMPR2 have a very distinctive profile, a new study reports. Due to bronchial arterial remodeling and new vessel formation, these patients are more prone to coughing up blood from the lungs or bronchial tubes (hemoptysis), and to showing increased pulmonary venous remodeling that correlates with pronounced changes in respiratory system vasculature.

The study, “BMPR2 mutation status influences bronchial vascular changes in pulmonary arterial hypertension,” was published in European Respiratory Journal.

Mutations in the gene BMPR2 are found in 70% of patients with hereditary PAH and in 11 %to 40% of those with non-hereditary PAH. This indicates that BMPR2 mutations are a predisposing factor for PAH development, but other factors are required to initiate the pulmonary vascular remodeling that is characteristic of the disease.

Previous studies have shown that patients carrying a BMPR2 mutation have early onset disease with more severe symptoms. These patients also have increased bronchial arterial hypertrophy compared to non-carriers of the mutation. Besides this evidence, though, the underling cause is unclear.

Researchers, in a study led by Peter Dorfmüller and colleagues in France, aimed to identify specific histological characteristics of PAH, or those found in tissues and cells of patients’ lungs, that could explain the relationship between BMPR2 mutations and PAH severity.

Forty-four PAH patients were enrolled in the study, of whom 23 were positive for BMPR2 mutations. When comparing the two groups, carriers versus non-carriers, researchers could not find any differences in age at diagnosis. Both groups also presented similar blood flow characteristics, except for pulmonary vascular resistance at diagnosis, which was higher in carriers. BMPR2 mutation carriers also had more frequent episodes of hemoptysis compared to non-carriers (43% versus 14%).

Looking carefully at lung tissue characteristics, the researchers found that PAH carriers had a similar degree of pulmonary arterial remodeling compared to non-carriers. Consistent with these results, similar vascular inflammation levels were seen in the two groups. Still, researchers found that 10 (43.5%) of the BMPR2 carriers and two (9.5%) of the non-carriers had singular large fibrovascular lesions, which are closely related to the systemic lung vasculature. Importantly, patients carrying BMPR2 mutations presented an increased bronchial arterial hypertrophy/dilatation (in which bronchial arteries become thicker and enlarged),  and bronchial microvessel density (a measure that reflects the number of blood vessels).

Of note was the fact that, irrespective of BMPR2 status, PAH patients who presented a history of hemoptysis showed a significant increase in the degree of bronchial artery hypertrophy/dilatation and bronchial microvessel density.

The research team, overall, was unable to define a biomarker capable of unequivocally distinguishing PAH patients with or without BMPR2 gene mutations, and stressed the need of further studies.

Nonetheless, the team concluded, “Our analysis provides evidence for the involvement of the pulmonary systemic circulation in BMPR2 mutation-related PAH. We show that BMPR2 mutation carriers are more prone to haemoptysis and that haemoptysis is closely correlated to bronchial arterial remodelling and angiogenesis [new blood vessel development]; in turn, pronounced changes in the systemic vasculature correlate with increased pulmonary venous remodelling, creating a distinctive profile in PAH patients harbouring a BMPR2 mutation.”