The Incremental Prognostic Value of Hepatocyte Growth Factor in First-Ever Acute Ischemic Stroke: An Early Link Between Growth Factor and Interleukins.

Fangfang Li,Rongliang Wang,Lingzhi Li,Ziping Han,Junfen Fan,Haiping Zhao,Zhenhong Yang,Yuyou Huang,Zhen Tao,Yangmin Zheng,Yumin Luo,Ping Liu,Sijia Zhang

doi:10.3389/fneur.2021.691886

Abstract

Hepatocyte growth factor (HGF) is a potential prognostic factor for acute ischemic stroke (AIS). In this study, we sought to validate its earlier predictive accuracy within 24 h for first-ever AIS. Moreover, as HGF interacts with interleukins, their associations may lead to novel immunomodulatory therapeutic strategies. Patients with first-ever AIS (n = 202) within 24 h were recruited. Plasma HGF and related interleukin concentrations were measured by multiplex immunoassays. The primary and secondary outcomes were major disability (modified Rankin scale score ≥3) at 3 months after AIS and death, respectively. Elastic net regression was applied to screen variables associated with stroke outcome; binary multivariable logistic analysis was then used to explore the relationship between HGF level and stroke outcome. After multivariate adjustment, upregulated HGF levels were associated with an increased risk of the primary outcome (odds ratio, 7.606; 95% confidence interval, 3.090–18.726; p < 0.001). Adding HGF to conventional risk factors significantly improved the predictive power for unfavorable outcomes (continuous net reclassification improvement 37.13%, p < 0.001; integrated discrimination improvement 8.71%, p < 0.001). The area under the receiver operating characteristic curve value of the traditional model was 0.8896 and reached 0.9210 when HGF was introduced into the model. An elevated HGF level may also be a risk factor for mortality within 3 months poststroke. The HGF level was also positively correlated with IL-10 and IL-16 levels, and HGF before interaction with all interleukins was markedly negatively correlated with the lymphocyte/neutrophil ratio. HGF within 24 h may have prognostic potential for AIS. Our findings reinforce the link between HGF and interleukins.

Highlights

Ischemic stroke is a prevalent disease with high disability and mortality
hepatocyte growth factor (HGF) levels may be useful in diagnosing ischemic stroke as an earlier study shows that serum levels of HGF in patients with cerebral infarction are significantly increased during the early stage and remain elevated until 7 d poststroke and that higher HGF concentrations are correlated with lower gains in the Stroke Impairment Assessment Set in stroke rehabilitation
Only plasma HGF remained an independent predictor of unfavorable outcome (p < 0.001) with a higher adjusted odds ratios (ORs) of 7.606 (3.090– 18.726)

Summary

Introduction

Ischemic stroke is a prevalent disease with high disability and mortality. The current treatments for acute ischemic stroke (AIS) are intravenous administration of tissue plasminogen activator (t-PA) and endovascular treatment to recanalize the blood flow. Circulating HGF levels can be referred to predict the risk of ischemic stroke [3]. Serum HGF levels were shown to be associated with poor prognosis at 3 months independent of stroke severity, especially in patients with AIS without heparin pretreatment [5]. HGF was independently associated with death and major disability in patients with AIS with dyslipidemia [6]. These studies excluded patients undergoing anticoagulation therapy because heparin has antifibrotic activity, mediated by the cellular secretion of HGF [7], and HGF is activated by t-PA [8], which abates its prognostic value. The patients in the above studies were recruited within 48 h of symptom onset; HGF level is already increased within 24 h [9]

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Results

Conclusion