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Targeted Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension

Myriam Amsallem, Andrew J. Sweatt, Jennifer Arthur Ataam, Julien Guihaire, Florence Lecerf, Mélanie Lambert, Maria Rosa Ghigna, Md Khadem Ali, Yuqiang Mao, Elie Fadel, Marlene Rabinovitch, Vinicio de Jesus Perez, Edda Spiekerkoetter, Olaf Mercier, Francois Haddad, Roham T. Zamanian
European Respiratory Journal 2020; DOI: 10.1183/13993003.02428-2020
Myriam Amsallem
1Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
2Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
3Vera Moulton Wall Center at Stanford, Stanford University School of Medicine, Stanford, CA, USA
8Both first authors and both senior authors contributed equally
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Andrew J. Sweatt
3Vera Moulton Wall Center at Stanford, Stanford University School of Medicine, Stanford, CA, USA
4Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA
8Both first authors and both senior authors contributed equally
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Jennifer Arthur Ataam
1Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
2Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
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Julien Guihaire
5Research and Innovation Laboratory, INSERM U999, Marie Lannelongue Hospital, Paris Sud Saclay University, Le Plessis Robinson, France
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Florence Lecerf
5Research and Innovation Laboratory, INSERM U999, Marie Lannelongue Hospital, Paris Sud Saclay University, Le Plessis Robinson, France
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Mélanie Lambert
5Research and Innovation Laboratory, INSERM U999, Marie Lannelongue Hospital, Paris Sud Saclay University, Le Plessis Robinson, France
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Maria Rosa Ghigna
6Division of Pathology, Marie Lannelongue Hospital, Le Plessis Robinson, France
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  • ORCID record for Maria Rosa Ghigna
Md Khadem Ali
3Vera Moulton Wall Center at Stanford, Stanford University School of Medicine, Stanford, CA, USA
4Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA
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Yuqiang Mao
3Vera Moulton Wall Center at Stanford, Stanford University School of Medicine, Stanford, CA, USA
4Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA
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Elie Fadel
6Division of Pathology, Marie Lannelongue Hospital, Le Plessis Robinson, France
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Marlene Rabinovitch
3Vera Moulton Wall Center at Stanford, Stanford University School of Medicine, Stanford, CA, USA
7Division of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
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Vinicio de Jesus Perez
3Vera Moulton Wall Center at Stanford, Stanford University School of Medicine, Stanford, CA, USA
4Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA
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Edda Spiekerkoetter
3Vera Moulton Wall Center at Stanford, Stanford University School of Medicine, Stanford, CA, USA
4Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA
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Olaf Mercier
5Research and Innovation Laboratory, INSERM U999, Marie Lannelongue Hospital, Paris Sud Saclay University, Le Plessis Robinson, France
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Francois Haddad
1Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
2Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
3Vera Moulton Wall Center at Stanford, Stanford University School of Medicine, Stanford, CA, USA
8Both first authors and both senior authors contributed equally
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Roham T. Zamanian
3Vera Moulton Wall Center at Stanford, Stanford University School of Medicine, Stanford, CA, USA
4Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA
8Both first authors and both senior authors contributed equally
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Abstract

No prior proteomic screening study has centered on the right ventricle (RV) in pulmonary arterial hypertension (PAH). This study investigates the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH.

Plasma proteomic profiling was performed using multiplex immunoassay in 121 PAH patients (discovery cohort) and 76 patients (validation cohort). The association between proteomic markers and RHMP (defined by the Mayo right heart score [combining RV strain, New York Heart Association NYHA class and NT-proBNP] and Stanford score [RV end-systolic remodelling index, NYHA and NT-proBNP]) was assessed by partial least squares regression. Biomarkers expressions were measured in RV samples from PAH patients and controls, and pulmonary artery banding (PAB) mice.

High levels of hepatic growth factor (HGF), stem cell growth factor beta, nerve growth factor and stromal derived factor-1 were associated with worse Mayo and Stanford scores independently from pulmonary resistance or pressure in both cohorts (the validation cohort had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added value to the REVEAL score in the prediction of death, transplant, or hospitalisation at 3 years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams.

High plasma HGF levels are associated with RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH. Assessing plasma HGF levels might identify patients at risk for heart failure who warrant closer follow-up and intensified therapy.

Footnotes

This 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.

Conflict of interest: Dr. Yan reports grants from National Institutes of Health, during the conduct of the study;.

Conflict of interest: Dr. Amsallem has nothing to disclose.

Conflict of interest: Dr. Sweatt has nothing to disclose.

Conflict of interest: Dr. ARTHUR ATAAM has nothing to disclose.

Conflict of interest: Dr. Guihaire MD PhD has nothing to disclose.

Conflict of interest: Dr. LECERF has nothing to disclose.

Conflict of interest: Dr. LAMBERT PHD has nothing to disclose.

Conflict of interest: Dr. Ghigna has nothing to disclose.

Conflict of interest: Dr. Ali has nothing to disclose.

Conflict of interest: Dr. Mao has nothing to disclose.

Conflict of interest: Dr. FADEL has nothing to disclose.

Conflict of interest: Dr. RABINOVITCH has nothing to disclose.

Conflict of interest: Dr. de Jesus Perez has nothing to disclose.

Conflict of interest: Dr. Spiekerkoetter has nothing to disclose.

Conflict of interest: Dr. MERCIER has nothing to disclose.

Conflict of interest: Dr. HADDAD has nothing to disclose.

Conflict of interest: Dr. Zamanian has nothing to disclose.

  • Received June 20, 2020.
  • Accepted October 6, 2020.
  • Copyright ©ERS 2020
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Targeted Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension
Myriam Amsallem, Andrew J. Sweatt, Jennifer Arthur Ataam, Julien Guihaire, Florence Lecerf, Mélanie Lambert, Maria Rosa Ghigna, Md Khadem Ali, Yuqiang Mao, Elie Fadel, Marlene Rabinovitch, Vinicio de Jesus Perez, Edda Spiekerkoetter, Olaf Mercier, Francois Haddad, Roham T. Zamanian
European Respiratory Journal Jan 2020, 2002428; DOI: 10.1183/13993003.02428-2020

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Targeted Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension
Myriam Amsallem, Andrew J. Sweatt, Jennifer Arthur Ataam, Julien Guihaire, Florence Lecerf, Mélanie Lambert, Maria Rosa Ghigna, Md Khadem Ali, Yuqiang Mao, Elie Fadel, Marlene Rabinovitch, Vinicio de Jesus Perez, Edda Spiekerkoetter, Olaf Mercier, Francois Haddad, Roham T. Zamanian
European Respiratory Journal Jan 2020, 2002428; DOI: 10.1183/13993003.02428-2020
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