Utility of Hepatocyte Growth Factor as a Biomarker for Early Diagnosis of Pulmonary Artery Hypertension

Liang, Ming-Ting; Pang, Ying; Zhang, Shuguang; Zhang, Mei

doi:10.1007/s40291-016-0214-3

Cited by 8 publications

(8 citation statements)

References 25 publications

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“…These alterations collectively suggest very early cardiac damage reflected in plasma HGF levels, which could be a result of starting pressure overload from damaged pulmonary arteries, although we cannot exclude also direct monocrotaline cardiotoxicity 24. Increased plasma HGF were reported in patients with various cardiovascular and pulmonary disorders 16, 17, 25, 26, as well as in patients with PH 19. In patients with PAH, plasma levels of HGF correlated with PAH severity, although a relation between HGF and duration of PAH was not studied 19.…”

Section: Discussionmentioning

confidence: 82%

“…Increased plasma HGF were reported in patients with various cardiovascular and pulmonary disorders 16, 17, 25, 26, as well as in patients with PH 19. In patients with PAH, plasma levels of HGF correlated with PAH severity, although a relation between HGF and duration of PAH was not studied 19. Our results confirm these findings and reveal that a rise of plasma HGF precedes the deterioration of RV function during the disease development and is in line with significantly rising Nppb expression in RV even in settings of stable RV pressure.…”

Section: Discussionmentioning

confidence: 99%

“…HGF has been suggested as a potential predictor of mortality in heart failure patients 16, hypertension severity 17 and could also be relevant in diagnostics of PH 18. HGF plasma levels correlated with mean pulmonary arterial pressure and HGF was detectable already at early stages of the disease 19, making it a potential biomarker candidate. However, its relation to target organ damage during disease progression remains unclear.…”

Section: Introductionmentioning

confidence: 99%

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Hepatocyte growth factor plays a particular role in progression of overall cardiac damage in experimental pulmonary hypertension

et al. 2019

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Background : HGF/MET pathway may have a role in pulmonary hypertension (PH). However, the link between the pathway and development of target organ damage in PH remains elusive. We aimed to demonstrate the relation between plasma HGF and HGF/MET tissue expressions in affected organs during PH progression. Methods : 12 weeks old male Wistar rats were injected with monocrotaline (MCT, 60 mg/kg, s.c.) to induce PH and sacrificed after 1, 2 and 4 weeks. Controls received saline. mRNA levels of HGF regulatory complex (Hgf, Met, Hgfa, Hai-1, Hai-2) were determined in right and left ventricles (RV, LV), lungs, pulmonary artery and liver by RT-qPCR. HGF protein levels in plasma were analysed by ELISA. Results : PH development was associated with a progressive elevation of HGF plasma levels that correlated with relative RV mass. Furthermore, Hgf mRNA expressions at week 4 were upregulated solely in the cardiac ventricles while being downregulated in a. pulmonalis , lungs and liver. Met and Hai-1/Hai-2 followed a similar pattern and were upregulated in cardiac ventricles, where Hgfa remained unchanged, but downregulated in lungs. Conclusion : We suggest that cardiac overexpression of Hgf might contribute to increased plasma HGF in MCT-induced PH. HGF could be exploited as a cardiospecific biomarker and HGF/MET pathway as a target in drug discovery for PH.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hepatocyte growth factor plays a particular role in progression of overall cardiac damage in experimental pulmonary hypertension

et al. 2019

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“…HGF is a pluripotent mitogenic protein, whose expression in blood was found to be increased in the present as well as previous PAH populations [ 14 ]. Nonetheless, this growth factor is suggested to have protective roles in PAH [ 6 ].…”

Section: Discussionmentioning

confidence: 83%

“…Fibroblast growth factor-2 is associated with pulmonary artery smooth muscle cell proliferation and is increased in blood samples from PAH patients [ 2 , 11 ]. However, hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF)-A, which are also upregulated in blood samples from PAH patients, are suggested to exert protective effects in PAH [ 4 – 6 , 12 – 14 ]. Finally, although the role for stem cell factor (SCF), a ligand for the receptor tyrosine kinase c-Kit [ 15 ], remains unclear in pulmonary hypertension, c-Kit + progenitor cells are known to accumulate in remodelled vessels in PAH [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

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

Bouzina

Rådegran

2018

ERJ Open Res

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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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Targeted Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension

Amsallem

Sweatt

Ataam

et al. 2020

Preprint

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Rationale: No prior proteomic screening study has centered on the right ventricle (RV) in pulmonary arterial hypertension (PAH). Objectives: To identify the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH. Methods: Plasma proteomic profiling was performed using multiplex immunoassay in 121 PAH patients (discovery cohort from 2008-2011) and 76 (validation cohort from 2012-2014). The association between proteomic markers and RHMP (defined by the Mayo right heart score [combining RV strain, NYHA and NT-proBNP] and Stanford score [RV end-systolic remodeling index, NYHA and NT-proBNP]) was assessed by partial least squares regression. Expression levels of biomarkers were measured in RV samples from PAH patients undergoing transplant and controls, and mice subjected to pulmonary artery banding (PAB). Measurements and Main Results: High levels of hepatic growth factor (HGF), stem cell growth factor beta, nerve growth factor and stromal derived factor-1 were significantly associated with worse Mayo and Stanford scores but not with pulmonary vascular resistance or pressure in both discovery and validation cohorts (this latter had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added incremental value to the REVEAL score in the prediction of death, transplant, or hospitalization 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. Conclusion: High plasma HGF levels are associated with a RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH.

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Utility of Hepatocyte Growth Factor as a Biomarker for Early Diagnosis of Pulmonary Artery Hypertension

Abstract: Plasma levels of HGF in PAH patients with mild disease were significantly higher than those in healthy controls, suggesting that plasma HGF has potential utility as a diagnostic biomarker for early PAH.

Cited by 8 publications

References 25 publications

Hepatocyte growth factor plays a particular role in progression of overall cardiac damage in experimental pulmonary hypertension

Hepatocyte growth factor plays a particular role in progression of overall cardiac damage in experimental pulmonary hypertension

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

Targeted Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension

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