BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis. Issue 2 (February 2016)

• Record Type: Journal Article
• Authors: Evans, Jonathan D W; Girerd, Barbara; Montani, David; Wang, Xiao-Jian; Galiè, Nazzareno; Austin, Eric D; Elliott, Greg; Asano, Koichiro; Grünig, Ekkehard; Yan, Yi; Jing, Zhi-Cheng; Manes, Alessandra; Palazzini, Massimiliano; Wheeler, Lisa A; Nakayama, Ikue; Satoh, Toru; Eichstaedt, Christina; Hinderhofer, Katrin; Wolf, Matthias; Rosenzweig, Erika B; Chung, Wendy K; Soubrier, Florent; Simonneau, Gérald; Sitbon, Olivier; Gräf, Stefan; Kaptoge, Stephen; Di Angelantonio, Emanuele; Humbert, Marc; Morrell, Nicholas W
• Is Part Of: Lancet. Volume 4:Issue 2(2016)
• Page Start: 129
• Page End: 137
• Publication Date: 2016-02
• Subjects: Respiratory organs -- Diseases -- Periodicals; 616.2005
• DOI: 10.1016/S2213-2600(15)00544-5
• Languages: English
• ISSNs: 2213-2600

Abstract

Summary: Background: Mutations in the gene encoding the bone morphogenetic protein receptor type II ( BMPR2 ) are the commonest genetic cause of pulmonary arterial hypertension (PAH). However, the effect of BMPR2 mutations on clinical phenotype and outcomes remains uncertain. Methods: We analysed individual participant data of 1550 patients with idiopathic, heritable, and anorexigen-associated PAH from eight cohorts that had been systematically tested for BMPR2 mutations. The primary outcome was the composite of death or lung transplantation. All-cause mortality was the secondary outcome. Hazard ratios (HRs) for death or transplantation and all-cause mortality associated with the presence of BMPR2 mutation were calculated using Cox proportional hazards models stratified by cohort. Findings: Overall, 448 (29%) of 1550 patients had a BMPR2 mutation. Mutation carriers were younger at diagnosis (mean age 35·4 [SD 14·8] vs 42·0 [17·8] years), had a higher mean pulmonary artery pressure (60·5 [13·8] vs 56·4 [15·3] mm Hg) and pulmonary vascular resistance (16·6 [8·3] vs 12·9 [8·3] Wood units), and lower cardiac index (2·11 [0·69] vs 2·51 [0·92] L/min per m 2 ; all p<0·0001). Patients with BMPR2 mutations were less likely to respond to acute vasodilator testing (3% [10 of 380] vs 16% [147 of 907]; p<0·0001). Among the 1164 individuals with available survival data, age-adjusted and sex-adjusted HRs comparing BMPR2 mutation carriers with non-carriers were 1·42 (95% CI 1·15–1·75; p=0·0011) for the composite of death or lung transplantation and 1·27 (1·00–1·60; p=0·046) for all-cause mortality. These HRs were attenuated after adjustment for potential mediators including pulmonary vascular resistance, cardiac index, and vasoreactivity. HRs for death or transplantation and all-cause mortality associated with BMPR2 mutation were similar in men and women, but higher in patients with a younger age at diagnosis (p=0·0030 for death or transplantation, p=0·011 for all-cause mortality). Interpretation: Patients with PAH and BMPR2 mutations present at a younger age with more severe disease, and are at increased risk of death, and death or transplantation, compared with those without BMPR2 mutations. Funding: Cambridge NIHR Biomedical Research Centre, Medical Research Council, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, INSERM, Université Paris-Sud, Intermountain Research and Medical Foundation, Vanderbilt University, National Center for Advancing Translational Sciences, National Institutes of Health, National Natural Science Foundation of China, and Beijing Natural Science Foundation.