BMPR2 variants in pulmonary arterial hypertension. Are they really worrisome?

Abstract

Abstract Background Pulmonary arterial hypertension (PAH) is a rare and severe disease. The discovery of the gene encoding Bone Morphogenetic Protein Receptor Type 2 (BMPR2) in 2000 was the first evidence of an association between genetics and PAH. BMPR2 mutation carriers are younger and have higher haemodynamic severity, determining higher risk than sporadic cases. In the last few years, novel genetic variants have been identified. The risk of mortality of the currently known mutations is scarce. Purpose To describe the role of gene variants regarding long-term survival in a cohort of PAH patients. Methods We included patients diagnosed with PAH between January 2011-December 2020, following the ESC/ERC Guidelines recommendations. At least one genetic study was available in included individuals. Pulmonary venooclusive disease, PAH associated with congenital heart disease, or connective tissue disorders were excluded. Three groups were compared: no mutation, BMPR2 carriers and other genetic variants. Comparison of qualitative and quantitative variables was done by Chi-square test and ANOVA test, respectively. Crude and adjusted Log-rank test was performed for the evaluation of mortality. Results 361 were finally included. The most frequent gene variant was BMPR2. Among the eight other gene variants, there were 2 cases of KCKN3, 2 of ACVRL1, and 1 case of KCNA5, TBX4, CPS1, and GDF2. BMPR2 and the rest of mutation carriers were younger at diagnosis and had worse haemodynamic parameters than non-carriers. Nevertheless, these patients tended to perform higher distances in the 6-minute walk test. Interestingly, BMPR2 patients had higher DLCO values at diagnosis (table). After 104.1±77.2 months of follow-up, there was a tendency for BMPR2 carriers toward lower crude free survival of mortality or lung transplantation. Nevertheless, this survival benefit disappears when adjusted by age (Table, figure). Conclusions The diagnostic yields of genetic analysis for pathogenic or likely pathogenic variants in idiopathic PAH are approximately 11%. BMPR2 is the most frequent causal gene. These patients are associated with marked haemodynamic impairment. Nevertheless, its younger age probably determines the better long-term results regarding mortality or lung transplantation observed when comparing these results with sporadic patients or those carrying other mutations. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Rio Hortega grant. Instituto de Salud Carlos III (ISCIII), Ministry of Science and Innovation, Spanish Government.