PT - JOURNAL ARTICLE AU - Tóth, Eszter N. AU - Celant, Lucas R. AU - Niglas, Marili AU - Jansen, Samara AU - Tramper, Jelco AU - Baxan, Nicoleta AU - Ashek, Ali AU - Wessels, Jeroen N. AU - Marcus, J. Tim AU - Meijboom, Lilian J. AU - Houweling, Arjan C. AU - Nossent, Esther J. AU - Aman, Jurjan AU - Grynblat, Julien AU - Perros, Frédéric AU - Montani, David AU - Vonk Noordegraaf, Anton AU - Zhao, Lan AU - de Man, Frances S. AU - Bogaard, Harm Jan TI - Deep phenotyping of unaffected carriers of pathogenic <em>BMPR2 variants</em> screened for pulmonary arterial hypertension AID - 10.1183/13993003.00442-2024 DP - 2024 Jan 01 TA - European Respiratory Journal PG - 2400442 4099 - http://erj.ersjournals.com/content/early/2024/06/27/13993003.00442-2024.short 4100 - http://erj.ersjournals.com/content/early/2024/06/27/13993003.00442-2024.full AB - 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 Bmpr2Δ71Ex1/+ 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. Bmpr2Δ71Ex1/+ 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&lt;0.001), 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 Bmpr2Δ71Ex1/+ transgenic rats. Future efforts in establishing an effective screening protocol for individuals at risk for developing PAH warrants longer follow-up periods.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflicts of interest: H-J. Bogaard reports support for the present study from Royal Netherlands Academy of Sciences (CVON-2017-10 Dolphin-Genesis), grants from MSD, Ferrer, Janssen, Dutch Federation of University Medical Centres, Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON-2012-08 PHAEDRA &amp; CVON-2018-29 PHAEDRA-IMPACT).Conflicts of interest: F. de Man reports support for the present study from Royal Netherlands Academy of Sciences (CVON-2017-10 Dolphin-Genesis), grants from Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, Netherlands Organisation for Health Research and Development, The Netherlands Organization for Scientific Research (NWO-VICI: 918.16.610, NWO-VIDI: 917.18.338), Royal Netherlands Academy of Sciences (CVON-2012-08 PHAEDRA &amp; CVON-2018-29 PHAEDRA-IMPACT) and Dutch Heart Foundation (Post doc Dekker 2018T05).Conflicts of interest: L. Zhao reports grants from British Heart Foundation (PG/18/2/33446 and BHF RE/18/4/34215).Conflicts of interest: D. Montani reports grants from Janssen, MSD, and Acceleron, consultation fees from Janssen, MSD, Ferrer and Acceleron, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer, Janssen, Boerhinger, Chiesi, GSK, Ferrer and Merck MSD.Conflicts of interest: F. Perros reports grants from French National Research Agency (ANR-20-CE14-0006), and INSERM (International Research Project (IRP) (Paris – Porto Pulmonary Hypertension Collaborative Laboratory (3PH)).Conflicts of interest: J. Grynblat reports research grants from Janssen, MSD and Ferrer.Conflicts of interest: A. Ashek reports research grants from Janssen, MSD and Ferrer.Conflicts of interest: N. Baxan reports research grants from Janssen, MSD and Ferrer.Conflicts of interest: M. Niglas reports research grants from Janssen, MSD and Ferrer.Conflicts of interest: A. Vonk Nordegraaf reports research grants from Janssen, MSD and Ferrer.Conflicts of interest: The remaining authors have nothing to disclose.