Deep phenotyping of unaffected carriers of pathogenic BMPR2 variants screened for pulmonary arterial hypertension
Pathogenic variants in the gene encoding for are a major genetic risk factor for heritable pulmonary arterial hypertension. Owing to incomplete penetrance, deep phenotyping of unaffected carriers of a pathogenic variant through multimodality screening may aid in early diagnosis and identify suscepti...
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| Published in | The European respiratory journal Vol. 64; no. 4; p. 2400442 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
European Respiratory Society
01.10.2024
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 0903-1936 1399-3003 1399-3003 |
| DOI | 10.1183/13993003.00442-2024 |
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| Abstract | Pathogenic variants in the gene encoding for
are a major genetic risk factor for heritable pulmonary arterial hypertension. Owing to incomplete penetrance, deep phenotyping of unaffected carriers of a pathogenic
variant through multimodality screening may aid in early diagnosis and identify susceptibility traits for future development of pulmonary arterial hypertension.
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
rat model was employed to validate findings from humans.
Unaffected carriers had lower indexed right ventricular end-diastolic (79.5±17.6 mL·m
62.7±15.3 mL·m
; p=0.001), end-systolic (34.2±10.5 mL·m
27.1±8.3 mL·m
; p=0.014) and left ventricular end-diastolic (68.9±14.1 mL·m
58.5±10.7 mL·m
; p=0.007) volumes than control subjects.
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
0.27±0.08 mmHg·mL
; p<0.001) and end-systolic elastance (0.28±0.07
0.35±0.10 mmHg·mL
; p=0.047) in addition to lower right ventricular pulmonary artery coupling (end-systolic elastance/arterial elastance 2.24±1.03
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.
Unaffected
mutation carriers have an altered cardiac phenotype mimicked in
transgenic rats. Future efforts to establish an effective screening protocol for individuals at risk for developing pulmonary arterial hypertension warrant longer follow-up periods. |
|---|---|
| AbstractList | 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.INTRODUCTIONPathogenic 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.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 Bmpr2Δ71Ex1/+ rat model was employed to validate findings from humans.METHODS28 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 Bmpr2Δ71Ex1/+ rat model was employed to validate findings from humans.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. Bmpr2Δ71Ex1/+ 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.RESULTSUnaffected 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. Bmpr2Δ71Ex1/+ 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.Unaffected BMPR2 mutation carriers have an altered cardiac phenotype mimicked in Bmpr2Δ71Ex1/+ transgenic rats. Future efforts to establish an effective screening protocol for individuals at risk for developing pulmonary arterial hypertension warrant longer follow-up periods.CONCLUSIONUnaffected BMPR2 mutation carriers have an altered cardiac phenotype mimicked in Bmpr2Δ71Ex1/+ 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. Unaffected BMPR2 mutation carriers have an altered cardiac phenotype, with slightly increased right ventricular contractility. In the screening of individuals susceptible to developing PAH, echocardiography and NT-proBNP are insufficient. https://bit.ly/3xtcD0w 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. Pathogenic variants in the gene encoding for are a major genetic risk factor for heritable pulmonary arterial hypertension. Owing to incomplete penetrance, deep phenotyping of unaffected carriers of a pathogenic variant through multimodality screening may aid in early diagnosis and identify susceptibility traits for future development of pulmonary arterial hypertension. 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 rat model was employed to validate findings from humans. Unaffected carriers had lower indexed right ventricular end-diastolic (79.5±17.6 mL·m 62.7±15.3 mL·m ; p=0.001), end-systolic (34.2±10.5 mL·m 27.1±8.3 mL·m ; p=0.014) and left ventricular end-diastolic (68.9±14.1 mL·m 58.5±10.7 mL·m ; p=0.007) volumes than control subjects. 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 0.27±0.08 mmHg·mL ; p<0.001) and end-systolic elastance (0.28±0.07 0.35±0.10 mmHg·mL ; p=0.047) in addition to lower right ventricular pulmonary artery coupling (end-systolic elastance/arterial elastance 2.24±1.03 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. Unaffected mutation carriers have an altered cardiac phenotype mimicked in transgenic rats. Future efforts to establish an effective screening protocol for individuals at risk for developing pulmonary arterial hypertension warrant longer follow-up periods. |
| Author | Grynblat, Julien de Man, Frances S. Zhao, Lan Bogaard, Harm Jan Marcus, J. Tim Aman, Jurjan Celant, Lucas R. Perros, Frédéric Montani, David Niglas, Marili Ashek, Ali Houweling, Arjan C. Jansen, Samara Tramper, Jelco Vonk Noordegraaf, Anton Nossent, Esther J. Tóth, Eszter N. Baxan, Nicoleta Meijboom, Lilian J. Wessels, Jeroen N. |
| AuthorAffiliation | 1 Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Pulmonary Medicine, Amsterdam, The Netherlands 4 Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Radiology and Nuclear Medicine, Amsterdam, The Netherlands 10 CarMeN Laboratory, INSERM U1060, INRAE U1397, Université Claude Bernard Lyon 1, Pierre-Bénite, France 5 Amsterdam UMC location AMC, Department of Human Genetics, Amsterdam, The Netherlands 6 INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Marie Lannelongue Hospital and Bicêtre Hospital, Le Plessis-Robinson, France 9 M3C-Necker, Hôpital Necker-Enfants Malades, AP-HP, Université de Paris Cité, Cardiologie Congénitale et Pédiatrique, Paris, France 8 Université Paris-Saclay, School of Medicine Gif-sur-Yvette, Gif-sur-Yvette, France 11 Contributed equally 2 Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Thrombosis, Amsterdam, The Netherlands 3 Imperial College London, National Heart and Lung Institute, London, |
| AuthorAffiliation_xml | – name: 2 Amsterdam Cardiovascular Sciences, Pulmonary Hypertension and Thrombosis, Amsterdam, The Netherlands – name: 3 Imperial College London, National Heart and Lung Institute, London, UK – name: 5 Amsterdam UMC location AMC, Department of Human Genetics, Amsterdam, The Netherlands – name: 7 AP-HP, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Center, Bicêtre Hospital, Le Kremlin-Bicêtre, France – name: 1 Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Pulmonary Medicine, Amsterdam, The Netherlands – name: 4 Amsterdam UMC location Vrije Universiteit Amsterdam, Department of Radiology and Nuclear Medicine, Amsterdam, The Netherlands – name: 8 Université Paris-Saclay, School of Medicine Gif-sur-Yvette, Gif-sur-Yvette, France – name: 10 CarMeN Laboratory, INSERM U1060, INRAE U1397, Université Claude Bernard Lyon 1, Pierre-Bénite, France – name: 6 INSERM UMR_S 999 “Pulmonary Hypertension: Pathophysiology and Novel Therapies”, Marie Lannelongue Hospital and Bicêtre Hospital, Le Plessis-Robinson, France – name: 11 Contributed equally – name: 9 M3C-Necker, Hôpital Necker-Enfants Malades, AP-HP, Université de Paris Cité, Cardiologie Congénitale et Pédiatrique, Paris, France |
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| Snippet | Pathogenic variants in the gene encoding for
are a major genetic risk factor for heritable pulmonary arterial hypertension. Owing to incomplete penetrance,... Pathogenic variants in the gene encoding for BMPR2 are a major genetic risk factor for heritable pulmonary arterial hypertension. Owing to incomplete... INTRODUCTION: Pathogenic variants in the gene encoding for BMPR2 are a major genetic risk factor for heritable pulmonary arterial hypertension (PAH). Due to... Summary of study protocol and main study findings. Unaffected carriers (UCs) of pathogenic BMPR2 variants and healthy family members (controls) were recruited... |
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| SubjectTerms | Adult Animals Bone Morphogenetic Protein Receptors, Type II - genetics Cardiac Catheterization Case-Control Studies Disease Models, Animal Echocardiography Exercise Test Female Genetic Predisposition to Disease Heterozygote Humans Hypertension, Pulmonary - genetics Hypertension, Pulmonary - physiopathology Life Sciences Magnetic Resonance Imaging Male Middle Aged Original s Phenotype Pulmonary Arterial Hypertension - genetics Pulmonary Arterial Hypertension - physiopathology Rats Rats, Transgenic |
| Title | Deep phenotyping of unaffected carriers of pathogenic BMPR2 variants screened for pulmonary arterial hypertension |
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