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

Abstract

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.

Summary of study protocol and main study findings. Unaffected carriers (UCs) of pathogenic BMPR2 variants and healthy family members (controls) were recruited for study participation after genetic counselling. A multimodality screening approach was employed with UCs undergoing an additional right heart catheterisation (RHC) at baseline and at the 4-year follow-up (T4). Main study findings include lower indexed right ventricular (RV) end-systolic volume (ESVi) and RV end-diastolic volume (EDVi) in UCs as well as a higher RV global circumferential strain (GCS) (red dots indicate phenoconverters). Haemodynamic and pressure–volume loop analysis showed higher RV end-systolic elastance (Ees), RV afterload (arterial elastance (Ea)) and altered RV pulmonary artery (PA) coupling (Ees/Ea) in UCs. During the study, two participants developed pulmonary arterial hypertension (PAH). MRI: magnetic resonance imaging; NT-proBNP: N-terminal pro-brain natriuretic peptide; NYHA: New York Heart Association; TTE: transthoracic echocardiography; V′_E: minute ventilation; V′_CO2: carbon dioxide production.

FIGURE 1

Schematic overview of the DOLPHIN-GENESIS study. MRI: magnetic resonance imaging; RHC: right heart catheterisation; T4: 4-year follow-up; TTE: transthoracic echocardiography.

FIGURE 2

Cardiac magnetic resonance imaging indices for unaffected carriers of a pathogenic BMPR2 variant compared to control participants. a) Indexed right ventricular (RV) end-diastolic volume (EDVi). b) Indexed RV end-systolic volume (ESVi). c) RV global circumferential strain (GCS). Red dots indicate phenoconverters. *: p<0.05; **: p<0.01; ***: p<0.001.

FIGURE 3

Cardiac volumetric and functional values for wild-type (WT) and Bmpr2 (Bmpr2^Δ71Ex1/+) rats. a) Mid-ventricular cardiac magnetic resonance imaging images from WT (n=5) and Bmpr2^Δ71Ex1/+ transgenic (n=6) rats at end-diastole (ED) and end-systole (ES). b) Right ventricular (RV) and left ventricular (LV) indexed end-diastolic volume (EDVi), indexed stroke volume (SVi), ejection fraction (EF), ventricular–arterial coupling index (SV/ESV) and mass index (Mi) values, all corrected for body surface area. *: p<0.05.

FIGURE 4

Comparison of haemodynamic parameters and pressure–volume relationships between unaffected carriers of a pathogenic BMPR2 variant and healthy control patients. a) Mean pulmonary artery pressure (mPAP). b) Arterial elastance (Ea). c) End-systolic elastance (Ees). d) Ees/Ea ratio. Red dots indicate phenoconverters. *: p<0.05; **: p<0.01; ***: p<0.001.