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

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Tóth, E. N. | Celant, L. R. | Niglas, M. | Jansen, S. | Tramper, J. | Baxan, N. | Ashek, A. | Wessels, J. N. | Marcus, J. T. | Meijboom, L. J. | Houweling, A. C. | Nossent, E. J. | Aman, J. | Grynblat, J. | Perros, F. | Montani, D. | Vonk Noordegraaf, A. | Zhao, L. | Man, F. S., De | Bogaard, H. J.

Edité par CCSD ; European Respiratory Society -

International audience. INTRODUCTION: Pathogenic variants in the gene encoding for BMPR2 are a major genetic risk factor for heritable pulmonary arterial hypertension (PAH). Due to incomplete penetrance, deep-phenotyping of unaffected carriers (UCs) of a pathogenic BMPR2 variant through multi-modality screening may aid in early diagnosis and identify susceptibility traits for future development of PAH. METHODS: 28 UCs (44±16 years, 57% female) and 21 healthy controls (43±18 years, 48% female) underwent annual screening, including cardiac magnetic resonance imaging (cMRI), transthoracic echocardiography (TTE), cardiopulmonary exercise testing (CPET) and right heart catheterization (RHC). Right ventricular (RV) pressure-volume (PV) 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 in humans. RESULTS: UCs had lower indexed right ventricular end-diastolic (80±18 mL·m(-2) versus 64±14 mL·m(-2);p= 0.003), end-systolic (34±11 mL·m(-2) versus 27±8 mL·m(-2);p=0.024) and left end-diastolic volumes (69±14 mL·m(-2) versus 60±11 mL·m(-2);p=0.019) than control subjects. Bmpr2(Δ71Ex1/+) rats were also observed to have smaller cardiac volumes than WT rats. PV loop analysis showed significantly higher afterload (Ea) (0.15±0.06 versus 0.27±0.08; p\textless0.001), and end-systolic elastance (Ees) 0.28±0.07 versus 0.35±0.10; p=0.047) in addition to lower RV-pulmonary artery coupling (Ees/Ea)(2.24±1.03 versus 1.36±0.37; p=0.006) in UCs. During the 4-year follow-up period, two UCs developed PAH with normal NT-proBNP and TTE indices at diagnosis. CONCLUSION: Unaffected BMPR2 mutation carriers have an altered cardiac phenotype mimicked in Bmpr2(Δ71Ex1/+) transgenic rats. Future efforts in establishing an effective screening protocol for individuals at risk for developing PAH warrants longer follow-up periods.

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