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Low plasma stem cell factor combined with high transforming growth factor-α identifies high-risk patients in pulmonary arterial hypertension

Bouzina, Habib LU and Rådegran, Göran LU (2018) In ERJ Open Research 4(4).
Abstract

In pulmonary arterial hypertension (PAH), severe vasoconstriction and remodelling of small pulmonary arteries result in high mortality. Receptor tyrosine kinases and their ligands, such as transforming growth factor (TGF)-α, modulate proliferation in PAH. Although the receptor tyrosine kinase c-Kit has been shown to be overexpressed in PAH, the expression and role of its ligand stem cell factor (SCF) remain unknown. However, low plasma SCF levels are known to be linked to higher cardiovascular mortality risk. Using proximity extension assays, we measured SCF and TGF-α in venous plasma from treatment-naïve PAH patients and healthy controls. Patients were stratified into risk classes based on PAH guidelines. Plasma SCF was decreased... (More)

In pulmonary arterial hypertension (PAH), severe vasoconstriction and remodelling of small pulmonary arteries result in high mortality. Receptor tyrosine kinases and their ligands, such as transforming growth factor (TGF)-α, modulate proliferation in PAH. Although the receptor tyrosine kinase c-Kit has been shown to be overexpressed in PAH, the expression and role of its ligand stem cell factor (SCF) remain unknown. However, low plasma SCF levels are known to be linked to higher cardiovascular mortality risk. Using proximity extension assays, we measured SCF and TGF-α in venous plasma from treatment-naïve PAH patients and healthy controls. Patients were stratified into risk classes based on PAH guidelines. Plasma SCF was decreased (p=0.013) and TGF-α was increased (p<0.0001) in PAH patients compared to controls. SCF correlated to pulmonary vascular resistance (r=-0.66, p<0.0001), cardiac index (r=0.66, p<0.0001), venous oxygen saturation (r=0.47, p<0.0008), mean right atrial pressure (r=-0.44, p<0.002) and N-terminal pro-brain natriuretic protein (r=-0.39, p<0.006). SCF was lower in "high-risk" compared to "intermediate-risk" (p=0.0015) or "low-risk" (p=0.0009) PAH patients. SCF and TGF-α levels combined (SCF/TGF-α) resulted in 85.7% sensitivity and 81.5% specificity for detecting high-risk patients (p<0.0001). Finally, REVEAL (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management) risk scores in PAH patients correlated to SCF/TGF-α levels (r=-0.50, p=0.0003). In conclusion, low plasma SCF combined with high TGF-α identifies high-risk PAH patients at baseline. Lower circulating SCF levels, which are associated with worse haemodynamics, may be related to the c-Kit accumulation previously observed in PAH.

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author
organization
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Contribution to journal
publication status
published
subject
in
ERJ Open Research
volume
4
issue
4
publisher
European Respiratory Society
ISSN
2312-0541
DOI
10.1183/23120541.00035-2018
language
English
LU publication?
yes
id
850a9d98-57af-4b2c-a472-c9151a6f249a
date added to LUP
2018-12-06 09:50:50
date last changed
2018-12-06 13:19:11
@article{850a9d98-57af-4b2c-a472-c9151a6f249a,
  abstract     = {<p>In pulmonary arterial hypertension (PAH), severe vasoconstriction and remodelling of small pulmonary arteries result in high mortality. Receptor tyrosine kinases and their ligands, such as transforming growth factor (TGF)-α, modulate proliferation in PAH. Although the receptor tyrosine kinase c-Kit has been shown to be overexpressed in PAH, the expression and role of its ligand stem cell factor (SCF) remain unknown. However, low plasma SCF levels are known to be linked to higher cardiovascular mortality risk. Using proximity extension assays, we measured SCF and TGF-α in venous plasma from treatment-naïve PAH patients and healthy controls. Patients were stratified into risk classes based on PAH guidelines. Plasma SCF was decreased (p=0.013) and TGF-α was increased (p&lt;0.0001) in PAH patients compared to controls. SCF correlated to pulmonary vascular resistance (r=-0.66, p&lt;0.0001), cardiac index (r=0.66, p&lt;0.0001), venous oxygen saturation (r=0.47, p&lt;0.0008), mean right atrial pressure (r=-0.44, p&lt;0.002) and N-terminal pro-brain natriuretic protein (r=-0.39, p&lt;0.006). SCF was lower in "high-risk" compared to "intermediate-risk" (p=0.0015) or "low-risk" (p=0.0009) PAH patients. SCF and TGF-α levels combined (SCF/TGF-α) resulted in 85.7% sensitivity and 81.5% specificity for detecting high-risk patients (p&lt;0.0001). Finally, REVEAL (Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management) risk scores in PAH patients correlated to SCF/TGF-α levels (r=-0.50, p=0.0003). In conclusion, low plasma SCF combined with high TGF-α identifies high-risk PAH patients at baseline. Lower circulating SCF levels, which are associated with worse haemodynamics, may be related to the c-Kit accumulation previously observed in PAH.</p>},
  author       = {Bouzina, Habib and Rådegran, Göran},
  issn         = {2312-0541},
  language     = {eng},
  number       = {4},
  publisher    = {European Respiratory Society},
  series       = {ERJ Open Research},
  title        = {Low plasma stem cell factor combined with high transforming growth factor-α identifies high-risk patients in pulmonary arterial hypertension},
  url          = {http://dx.doi.org/10.1183/23120541.00035-2018},
  volume       = {4},
  year         = {2018},
}