BMPR2 mutations affect outcomes of PAH patients

By Eleanor McDermid

Mutations in the bone morphogenetic protein receptor type II gene (BMPR2) affect not only the risk of developing pulmonary arterial hypertension (PAH) but also the severity and outcomes of the disease, shows a meta-analysis of individual patient data.

The analysis, which appears in The Lancet Respiratory Medicine, involves 1550 patients with idiopathic, heritable or anorexigen-associated PAH, 29% of whom had a BMPR2 mutation - the most common genetic cause of PAH.

Patients with BMPR2 mutations were younger when they presented with PAH symptoms than those without mutations, at an average of 35.4 versus 42.0 years. And they had more severe disease, with a significantly higher mean pulmonary artery pressure (60.5 vs 56.4 mmHg) and pulmonary vascular resistance (16.6 vs 12.9 Wood units) and lower cardiac index (2.11 vs 2.51 L/min per m²).

They were also less likely to respond to vasodilators, at 3% versus 16%, report Nicholas Morrell (University of Cambridge School of Clinical Medicine, UK) and study co-authors.

During a median 5.4-year follow-up, 354 of 1164 patients died and 74 required lung transplantation, with these outcomes being a significant 42% more likely in BMPR2 mutation carriers than noncarriers. They were also 27% more likely to die of any cause, and the effect on BMPR2 mutations on the risk of both outcomes was greater in younger than older patients.

The increased mortality and transplantation risk was driven mainly by the lower cardiac index in carriers versus noncarriers, which accounted for 65% of the increased death/transplantation risk and 79% of the increased all-cause mortality risk.

In a linked commentary, Jeremy Mazurek and Steven Kawut, from the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, USA, highlight this finding as "important as it confirms previous data showing the effect of cardiac index, a somewhat crude metric of right ventricular function, on survival in PAH in general, and in familial PAH specifically."

They add: "It also implicates mutations in BMPR2 as contributors to right ventricular dysfunction, perhaps via perturbations in right ventricular metabolism and lipotoxicity, as previously described."

Pulmonary vascular resistance and vasodilator responsiveness, when added to cardiac index, increased the proportion of excess risk accounted for to 71% for death/transplantation and 100% for all-cause mortality.

However, Mazurek and Kawut note that there was "moderate heterogeneity" in the analysis and that carrying BMPR2 mutations only amounted to about a 30-40% increased risk. "Thus, for the individual patient, the presence of a mutation might not have sufficient discriminatory power to tailor treatment or predict outcome", they say.

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