Elevated blood plasma levels of epinephrine, norepinephrine, tyrosine hydroxylase, TGFβ1, and TNFα associated with high-altitude pulmonary edema in an Indian population

Abstract

Biomarkers are essential to unravel the locked pathophysiology of any disease. This study investigated the role of biomarkers and their interactions with each other and with the clinical parameters to study the physiology of high-altitude pulmonary edema (HAPE) in HAPE-patients (HAPE-p) against adapted highlanders (HLs) and healthy sojourners, HAPE-controls (HAPE-c). For this, seven circulatory biomarkers, namely, epinephrine, norepinephrine, tyrosine hydroxylase, transforming growth factor beta 1, tumor necrosis factor alpha (TNFα), platelet-derived growth factor beta beta, and C-reactive protein (CRP), were measured in blood plasma of the three study groups. All the subjects were recruited at ~3,500 m, and clinical features such as arterial oxygen saturation (SaO2), body mass index, and mean arterial pressure were measured. Increased levels of epinephrine, norepinephrine, tyrosine hydroxylase, transforming growth factor-beta 1, and TNFα were observed in HAPE-p against the healthy groups, HAPE-c, and HLs (P<0.0001). CRP levels were decreased in HAPE-p against HAPE-c and HLs (P<0.0001). There was no significant difference or very marginal difference in the levels of these biomarkers in HAPE-c and HLs (P>0.01). Correlation analysis revealed a negative correlation between epinephrine and norepinephrine (P=4.6E-06) in HAPE-p and positive correlation in HAPE-c (P=0.004) and HLs (P=9.78E-07). A positive correlation was observed between TNFα and CRP (P=0.004) in HAPE-p and a negative correlation in HAPE-c (P=4.6E-06). SaO2 correlated negatively with platelet-derived growth factor beta beta (HAPE-p; P=0.05), norepinephrine (P=0.01), and TNFα (P=0.005) and positively with CRP (HAPE-c; P=0.02) and norepinephrine (HLs; P=0.04). Body mass index correlated negatively with epinephrine (HAPE-p; P=0.001) and positively with norepinephrine and tyrosine hydroxylase in HAPE-c (P<0.05). Mean arterial pressure correlated positively with TNFα in HAPE-p and norepinephrine in HLs (P<0.05). Receiver operating characteristic curve analysis yielded a positive predictive value for these biomarkers with HAPE (area under the curve >0.70, P<0.05). The results clearly suggest that increased plasma levels of these circulatory biomarkers associated with HAPE.

Keywords: HAPE; adaptation; biomarkers; correlation; high-altitude; sympathetic nervous system.

Figure 1

Pathway specifying the role of the studied biomarkers (1–7) in the progression of HAPE. Notes: Upward red arrows: the process or the molecule is upregulated. Downward red arrow: the process or the molecule is downregulated. *Dashed green arrow indicates it is not yet entirely known whether or not that inflammation occurs in HAPE. Abbreviations: HAPE, high-altitude pulmonary edema; TGFβ1, transforming growth factor beta 1; TNFα, tumor necrosis factor alpha; PDGF-ββ, platelet-derived growth factor beta beta; CRP, C-reactive protein; ECM, extracellular matrix; PAI1, plasminogen activator inhibitor 1; VSMCs, vascular smooth muscle cells; ROS, reactive oxygen species; ECs, endothelial cells.

Figure 2

Correlation analysis between SaO₂ and biomarkers in the three study groups. P<0.05 was considered significant. Notes: Sample size for biomarker correlations: HAPE-p, n=50; HAPE-c, n=33; HLs, n=23. Epinephrine (A), norepinephrine (B), tyrosine hydroxylase (C), TGFβ1 (D), TNFα (E), PDGF-ββ (F), and CRP (G). Abbreviations: SaO₂, arterial oxygen saturation; HAPE, high-altitude pulmonary edema; HAPE-p, HAPE-patients; HAPE-c, HAPE-controls; HLs, highlanders; TGFβ1, transforming growth factor beta 1; TNFα, tumor necrosis factor alpha; PDGF-ββ, platelet-derived growth factor beta beta; CRP, C-reactive protein.

Figure 3

Correlation analysis between BMI and biomarkers in the three study groups. Notes: Sample size for biomarker correlations: HAPE-p, n=50; HAPE-c, n=33; HLs, n=23. Epinephrine (A), norepinephrine (B), tyrosine hydroxylase (C), TGFβ1 (D), TNFα (E), PDGF-ββ (F), and CRP (G). Abbreviations: BMI, body mass index; HAPE, high-altitude pulmonary edema; HAPE-p, HAPE-patients; HAPE-c, HAPE-controls; HLs, highlanders; TGFβ1, transforming growth factor beta 1; TNFα, tumor necrosis factor alpha; PDGF-ββ, platelet-derived growth factor beta beta; CRP, C-reactive protein.

Figure 4

Correlation analysis between MAP and biomarkers in the three study groups. Notes: Sample size for biomarker correlations: HAPE-p, n=50; HAPE-c, n=33; HLs, n=23. Epinephrine (A), norepinephrine (B), tyrosine hydroxylase (C), TGFβ1 (D), TNF (E), PDGF-ββ (F), and CRP (G). Abbreviations: MAP, mean arterial pressure; HAPE, high-altitude pulmonary edema; HAPE-p, HAPE-patients; HAPE-c, HAPE-controls; HLs, highlanders; TGFβ1, transforming growth factor beta 1; TNFα, tumor necrosis factor alpha; PDGF-ββ, platelet-derived growth factor beta beta; CRP, C-reactive protein.

Figure 5

ROC curves for determining the prediction value of the studied biomarkers. Notes: AUC >0.70 was considered as benchmark for good predictive value of the biomarker. The analysis has been performed between HAPE-p and HAPE-c. Epinephrine (A), norepinephrine (B), TH (C), TGFβ1 (D), TNFα (E), and CRP (F). Abbreviations: ROC, receiver operating characteristic; AUC, area under the curve; HAPE, high-altitude pulmonary edema; HAPE-p, HAPE-patients; HAPE-c, HAPE-controls; TH, tyrosine hydroxylase; TGFβ1, transforming growth factor beta 1; TNFα, tumor necrosis factor alpha; CRP, C-reactive protein.

Figure 6

ROC curves for determining the prediction value of the studied biomarkers. Notes: AUC >0.70 was considered as benchmark for good predictive value of the biomarker. The analysis has been performed between HAPE-p and HLs. Epinephrine (A), norepinephrine (B), TH (C), TGFβ1 (D), TNFα (E), and CRP (F). Abbreviations: ROC, receiver operating characteristic; AUC, area under the curve; HAPE, high-altitude pulmonary edema; HAPE-p, HAPE-patients; HLs, highlanders; TH, tyrosine hydroxylase; TGFβ1, transforming growth factor beta 1; TNFα, tumor necrosis factor alpha; CRP, C-reactive protein.