Abstract
BackgroudPatients with acute ischemic stroke (AIS) often experience low serum free triiodothyronine (FT3), but the association of low FT3 with stroke severity, subtype and prognosis has not yet been thoroughly studied, and the molecular events underlying these clinical observation were also unclear.MethodsWe retrospectively collected 221 cases of AIS and 182 non-AIS cases with detailed clinical data from our department. FT3 concentrations were measured on admission to predict functional outcome within 3 months using multivariable models adjusted for other risk factors. Receiver operating characteristic (ROC) curves were calculated to define the best cutoff value of FT3 of stroke severity, subtypes and neurological outcome. Gene set enrichment, pathway mapping and network analyses of deferentially expressed genes (DEGs) were performed.ResultsFT3 was significantly decreased in AIS patients with National Institutes of Health Stroke Scale (NIHSS) > 3 and 3-months modified Rankin Scale (mRS) > 2. The cut-off value of FT3 for NIHSS on admission was 4.30 pmol/L. Also, FT3 level was significantly lower in large artery atherosclerosis (LAA) group and cardioembolism (CE) group than that in small vessel occlusion (SVO). FT3 value served as an independent predictor for neurological outcomes for which the cut-off value of FT3 was 4.38 pmol/l. Gene ontology (GO) analysis showed that the biological function of DEGs was mainly enriched in multicellur organism, neuron differentiation and cellular response to hypoxia. The cellular components were involved in extracelluar region, exosome and matrix, and the molecular functions were transcriptional activator activity, DNA binding and nuclear hormone receptor binding. Signal pathways analysis was indicative of neuroactive ligand-receptor interaction, thyroid hormone signaling pathway, and protein digestion and absorption these DEGs were involved in. Six related gene were identified as hubs from the protein-protein interaction (PPI) networks. Three modules were selected from PPI, of which MMP4, ADRA2C and EIF3E were recognized as the seed genes.ConclusionsLow FT3 value on admission was associated with stroke severity, subtype and prognosis. In addition, DEGs identified from bioinformatics analysis are likely to be candidates for elucidating clinical outcomes with low FT3, and provide us with therapeutic targets for improving stroke prognosis.
Highlights
Neuroendocrine system could be significantly altered in acute stroke status
Four hundred twelve patients were recruited to acute ischemic stroke (AIS) group according to inclusion criteria as follows: (1) age between 18 and 85 years; (2) stroke onset within 7 days before admission; (3) ischemic stroke confirmed by computerized tomography or magnetic resonance imaging at the time of admission
To avoid any confounding effects, 191 AIS patients were excluded according to the exclusion criteria including (a) no examination of diffusion-weighted image (DWI), inability to confirm the new characteristics of cerebral infarction (n = 78); (b) patients with haemorrhagic stroke, tumor, infection, inflammatory conditions, hematological diseases, and severe renal, liver or cardiopulmonary failure (n = 62); (c) patients with hyper- or hypothyroidism and treated with drugs known to interact with the thyroid gland (n = 51)
Summary
Neuroendocrine system could be significantly altered in acute stroke status. Most of the clinical studies related to neuroendocrine findings in AIS focus on the hypothalamic-pituitary-adrenocortical axis and related stress mechanism [1, 2]. It has reported that during diverse cardiovascular critical statuses, thyroid gland metabolism changed [3]. This problem was defined as non-thyroidal illnesssyndrome (NTIS), called low T3 syndrome, in which abnormalities of thyroid hormones occur due to non-thyroidal system disorder [4]. The role of low T3 in the prognosis of stroke patients is independent from well-established clinical prognostic indicators, suggesting that the low T3 syndrome can exert prognostic value above and beyond currently used stroke prediction models [8]. One of our study goals is to analyze the role of low FT3 on stroke prognosis and the association between low FT3 and clinical types of AIS
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