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Plasma receptor tyrosine kinase RET in pulmonary arterial hypertension diagnosis and differentiation

Säleby, Joanna LU ; Bouzina, Habib LU ; Ahmed, Salaheldin LU ; Lundgren, Jakob LU and Rådegran, Göran LU (2019) In ERJ Open Research 5(4).
Abstract

Background: Pulmonary arterial hypertension (PAH) is a serious disease exhibiting unspecific symptoms, as a result of which diagnosis is often delayed and prognosis is poor. The underlying pathophysiology includes vasoconstriction and remodelling of small pulmonary arteries. As receptor tyrosine kinases (RTKs) and their ligands have been shown to promote PAH remodelling, our aim was to evaluate if their plasma levels may be utilised to differentiate between various causes of pulmonary hypertension. Methods: 28 biomarkers involved in RTK signalling were measured using proximity extension assays in venous plasma from patients with PAH (n=48), chronic thromboembolic pulmonary hypertension (CTEPH) (n=20), pulmonary hypertension due to... (More)

Background: Pulmonary arterial hypertension (PAH) is a serious disease exhibiting unspecific symptoms, as a result of which diagnosis is often delayed and prognosis is poor. The underlying pathophysiology includes vasoconstriction and remodelling of small pulmonary arteries. As receptor tyrosine kinases (RTKs) and their ligands have been shown to promote PAH remodelling, our aim was to evaluate if their plasma levels may be utilised to differentiate between various causes of pulmonary hypertension. Methods: 28 biomarkers involved in RTK signalling were measured using proximity extension assays in venous plasma from patients with PAH (n=48), chronic thromboembolic pulmonary hypertension (CTEPH) (n=20), pulmonary hypertension due to diastolic (n=33) or systolic (n=36) heart failure and heart failure patients without pulmonary hypertension (n=15), as well as healthy controls (n=20). Results: Plasma proto-oncogene tyrosine-protein kinase receptor Ret (RET) was decreased (p<0.04) in PAH compared with all disease groups and controls. RET generated a sensitivity of 64.6% and a specificity of 81.6% for detecting PAH from other disease groups. PAH and the other pulmonary hypertension groups showed elevated plasma tyrosine-protein kinase MER (p<0.01), vascular endothelial growth factor (VEGF)-A (p<0.02), VEGF-D (p<0.01), placental growth factor (p<0.01), amphiregulin (p<0.02), hepatocyte growth factor (p<0.01) and transforming growth factor-α (p<0.05) and decreased VEGF receptor-2 (p<0.04) and epidermal growth factor receptor (p<0.01) levels compared with controls. Conclusion: Plasma RET differentiates patients with PAH from those with CTEPH, systolic or diastolic heart failure with or without pulmonary hypertension as well as healthy controls. Future studies would be of value to determine the clinical usefulness of RET as a biomarker and its link to PAH pathophysiology.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
ERJ Open Research
volume
5
issue
4
article number
00037
publisher
European Respiratory Society
external identifiers
  • pmid:31754623
ISSN
2312-0541
DOI
10.1183/23120541.00037-2019
project
Biomarkers in Pulmonary Hypertension
language
English
LU publication?
yes
id
553bf61b-f196-44e8-9952-435a5171b111
date added to LUP
2020-01-23 17:15:30
date last changed
2020-04-28 11:46:54
@article{553bf61b-f196-44e8-9952-435a5171b111,
  abstract     = {<p>Background: Pulmonary arterial hypertension (PAH) is a serious disease exhibiting unspecific symptoms, as a result of which diagnosis is often delayed and prognosis is poor. The underlying pathophysiology includes vasoconstriction and remodelling of small pulmonary arteries. As receptor tyrosine kinases (RTKs) and their ligands have been shown to promote PAH remodelling, our aim was to evaluate if their plasma levels may be utilised to differentiate between various causes of pulmonary hypertension. Methods: 28 biomarkers involved in RTK signalling were measured using proximity extension assays in venous plasma from patients with PAH (n=48), chronic thromboembolic pulmonary hypertension (CTEPH) (n=20), pulmonary hypertension due to diastolic (n=33) or systolic (n=36) heart failure and heart failure patients without pulmonary hypertension (n=15), as well as healthy controls (n=20). Results: Plasma proto-oncogene tyrosine-protein kinase receptor Ret (RET) was decreased (p&lt;0.04) in PAH compared with all disease groups and controls. RET generated a sensitivity of 64.6% and a specificity of 81.6% for detecting PAH from other disease groups. PAH and the other pulmonary hypertension groups showed elevated plasma tyrosine-protein kinase MER (p&lt;0.01), vascular endothelial growth factor (VEGF)-A (p&lt;0.02), VEGF-D (p&lt;0.01), placental growth factor (p&lt;0.01), amphiregulin (p&lt;0.02), hepatocyte growth factor (p&lt;0.01) and transforming growth factor-α (p&lt;0.05) and decreased VEGF receptor-2 (p&lt;0.04) and epidermal growth factor receptor (p&lt;0.01) levels compared with controls. Conclusion: Plasma RET differentiates patients with PAH from those with CTEPH, systolic or diastolic heart failure with or without pulmonary hypertension as well as healthy controls. Future studies would be of value to determine the clinical usefulness of RET as a biomarker and its link to PAH pathophysiology.</p>},
  author       = {Säleby, Joanna and Bouzina, Habib and Ahmed, Salaheldin and Lundgren, Jakob and Rådegran, Göran},
  issn         = {2312-0541},
  language     = {eng},
  month        = {10},
  number       = {4},
  publisher    = {European Respiratory Society},
  series       = {ERJ Open Research},
  title        = {Plasma receptor tyrosine kinase RET in pulmonary arterial hypertension diagnosis and differentiation},
  url          = {http://dx.doi.org/10.1183/23120541.00037-2019},
  doi          = {10.1183/23120541.00037-2019},
  volume       = {5},
  year         = {2019},
}