Deep phenotyping of unaffected carriers of pathogenic BMPR2 variants screened for pulmonary arterial hypertension.

Introduction: Pathogenic variants in the gene encoding for BMPR2 are a major genetic risk factor for heritable pulmonary arterial hypertension. Owing to incomplete penetrance, deep phenotyping of unaffected carriers of a pathogenic BMPR2 variant through multimodality screening may aid in early diagnosis and identify susceptibility traits for future development of pulmonary arterial hypertension.

Methods: 28 unaffected carriers (44±16 years, 57% female) and 21 healthy controls (44±18 years, 48% female) underwent annual screening, including cardiac magnetic resonance imaging, transthoracic echocardiography, cardiopulmonary exercise testing and right heart catheterisation. Right ventricular pressure-volume loops were constructed to assess load-independent contractility and compared with a healthy control group. A transgenic Bmpr2^Δ71Ex1/+ rat model was employed to validate findings from humans.

Results: Unaffected carriers had lower indexed right ventricular end-diastolic (79.5±17.6 mL·m^-2 versus 62.7±15.3 mL·m^-2; p=0.001), end-systolic (34.2±10.5 mL·m^-2 versus 27.1±8.3 mL·m^-2; p=0.014) and left ventricular end-diastolic (68.9±14.1 mL·m^-2 versus 58.5±10.7 mL·m^-2; p=0.007) volumes than control subjects. Bmpr2^Δ71Ex1/+ rats were also observed to have smaller cardiac volumes than wild-type rats. Pressure-volume loop analysis showed that unaffected carriers had significantly higher afterload (arterial elastance 0.15±0.06 versus 0.27±0.08 mmHg·mL^-1; p<0.001) and end-systolic elastance (0.28±0.07 versus 0.35±0.10 mmHg·mL^-1; p=0.047) in addition to lower right ventricular pulmonary artery coupling (end-systolic elastance/arterial elastance 2.24±1.03 versus 1.36±0.37; p=0.006). During the 4-year follow-up period, two unaffected carriers developed pulmonary arterial hypertension, with normal N-terminal pro-brain natriuretic peptide and transthoracic echocardiography indices at diagnosis.

Conclusion: Unaffected BMPR2 mutation carriers have an altered cardiac phenotype mimicked in Bmpr2^Δ71Ex1/+ transgenic rats. Future efforts to establish an effective screening protocol for individuals at risk for developing pulmonary arterial hypertension warrant longer follow-up periods.