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

Abstract

BackgroundPulmonary 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.Methods28 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).ResultsPlasma 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.ConclusionPlasma 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.

Endothelial Dysfunction in Pulmonary Hypertension: Cause or Consequence?

“…At last, the expression of the growth factor vascular endothelial growth factor (VEGF) and its receptor VEGF receptor 2 (VEGFR2) are found to be increased in ECs from plexiform lesions from iPAH patients. Additionally, the plasma levels of VEGF are found to be elevated in PH patients [ 101 , 102 ]. The relation between PAH and increased VEGF expression is still poorly understood.…”

Elevated plasma tyrosine kinases VEGF-D and HER4 in heart failure patients decrease after heart transplantation in association with improved haemodynamics

“…In clinical studies, high plasma VEGF-D differentiated PH-LHD from PAH, chronic thromboembolic PH (CTEPH) and controls, and a similar increase was related to PAH progression in systemic sclerosis patients [13,14]. Further, we have recently confirmed in a larger patient cohort that apart from the levels being highest in HF patients with reduced ejection fraction with PH, plasma VEGF-D elevations were also found in PAH and CTEPH patients compared to healthy controls [38]. Hence, it is reasonable to hypothesise that VEGF-D and involved signalling pathways may have a role in the reversibility of PVR and PAC in HF patients with or without related PH.…”

Plasma adrenomedullin peptides and precursor levels in pulmonary arterial hypertension disease severity and risk stratification

“…This may merely mirror the real-life situation where patients with left heart disease receive more of medications that might affect the renin–angiotensin–aldosterone system (RAAS) than patients with PAH or CTEPH. 22 An increased RAAS response is present in patients with PAH. 23 Pulmonary arteries and endothelial cells from PAH patients have been shown to have increased angiotensin II receptor type 1 (AT 1 receptor) expression and increased angiotensin II production, respectively.…”