Article Dans Une Revue European Respiratory Journal Année : 2024

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

N. Baxan
  • Fonction : Auteur
A. Ashek
  • Fonction : Auteur
L. Zhao
  • Fonction : Auteur

Résumé

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.

Dates et versions

inserm-04756440 , version 1 (28-10-2024)

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Citer

E. N. Tóth, L. R. Celant, M. Niglas, S. Jansen, J. Tramper, et al.. Deep phenotyping of unaffected carriers of pathogenic BMPR2 variants screened for pulmonary arterial hypertension. European Respiratory Journal, 2024, 64 (4), pp.2400442. ⟨10.1183/13993003.00442-2024⟩. ⟨inserm-04756440⟩
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