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The study covered in this summary was published in medRxiv.org as a preprint and has not yet been peer reviewed.

Key Takeaways

  • The study suggests genes involved in regulating immune response after ischemic stroke (IS) may impact long-term functional outcomes.

  • Whole transcriptome analysis of peripheral blood identified genes and networks associated with 90-day IS outcomes that were either good or poor.

  • Poor outcome gene modules were enriched in down-regulated T-cell and monocyte-specific genes and up-regulated neutrophil genes by modified Rankin Scale (mRS).

  • Good outcome modules were associated with erythroblasts and megakaryocytes.

  • Predictive genes were associated with platelet aggregation, release of coagulation factors, and potassium channel regulation.

Why This Matters

  • Predicting functional outcome in stroke is challenging because of its complexity and lack of prognostic models. Clinical and demographic variables only explain a portion of variance in long-term IS outcome. This study addressed a need to identify additional biomarkers to explain outcome variance.

  • The study identified early immune gene responses associated with 90-day outcomes to improve understanding of pathways involved in recovery mechanisms. The study identified biomarkers to potentially determine cause of IS. The biomarkers and can also be used potentially as treatment targets and predictors of IS outcomes.

  • Ultimately, findings can be used to develop a molecularly-based pilot machine learning model to predict long-term functional outcome after IS.

Study Design

  • The peripheral blood transciptome of patients after IS was studied to discover genes and pathways associated with 90-day outcomes.

  • Peripheral blood was drawn from 36 ischemic stroke patients at ≤ 3 hours, 5 hours, and 24 hours as part of the Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue-Type Plasminogen Activator (CLEAR) trial. Patients were treated with recombinant tissue plasminogen activator (rt-PA) with or without eptifibatide after the within-3-hour blood sample was obtained and had subsequent blood samples drawn at 5 and 24 hours.

  • A control population included Vascular Risk Factor Control subjects with one cardiovascular risk factor (hypertension, diabetes mellitus, hyperlipidemia) recruited from the Sex Age Variation in Vascular Functionality (SAVVY) trial.

  • Whole transcriptome analysis identified gene expression at 3 hours, naproxen patient teaching 5 hours, and 24 hours associated with 90-day mRS outcome and the NIH Stroke Scale outcome.  A 90-day mRS score was used to determine good (0-2) or poor (3-5) outcomes.

  • Weighted Gene Co-Expression Network Analysis (WGCNA) revealed modules associated with 90-day outcome. 

Key Results

  • The expression of 467, 526, and 571 genes measured at ≤ 3 hours, 5 hours, and 24 hours after IS, respectively, were associated with poor 90-day mRS outcome, while 49, 100 and 35 genes were associated with good mRS 90-day outcome measured at the same timepoints.

  • Poor outcomes were associated with up-regulated MMP9S100A12, interleukin-related and STAT3 pathways. 

  • Poor outcome modules were enriched in down-regulated T-cell and monocyte-specific genes and were also enriched in up-regulated neutrophil genes. Good outcome modules were associated with erythroblasts and megakaryocytes.

  • Using the difference in gene expression between 3 and 24 hours, 10 genes predicted 100% of patients with good 90-day mRS outcome and 67% with poor mRS outcome (AUC=0.88) in a validation set.

  • The predictors included AVPR1A, which mediates platelet aggregation, release of coagulation factors, and exacerbates the brain inflammatory response.

  • Another predictor was KCNK1 (TWIK-1), a member of a two-pore potassium channel family that likely modulates stroke outcomes. 

Limitations

  • Researchers suggested larger cohorts are needed to validate the findings from the study.

  • The cell-specific genes were identified in healthy participants and their expression patterns may change in a disease state.

  • Changes in cell counts of specific peripheral blood cell types have been reported after ischemic stroke and may affect outcome differences of expression.

  • Because all study participants received treatment after IS, the results cannot determine if treatment affected outcomes.

Disclosures

  • The study received no commercial funding.

  • None of the authors disclosed relevant financial relationships.

This is a summary of a preprint research study, “Peripheral Blood Gene Expression at 3 to 24 Hours Correlates With and Predicts 90-Day Outcome Following Human Ischemic Stroke,” written by researchers at the University of California at Davis, Sacramento, California on medRxiv, provided to you by Medscape. This study has not yet been peer reviewed. The full text of the study can be found on medRxiv.org.

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