MicroRNAs as biomarkers in spontaneous intracerebral hemorrhage: A systematic review of recent clinical evidence

Abstract

Objectives: Spontaneous intracerebral hemorrhage (SICH) is a subtype of stroke associated with high mortality and devastating disabilities. Therefore, identifying non-invasive biomarkers for SICH would have a tremendous clinical impact. MicroRNAs (miRNAs) are non-coding single-stranded RNAs containing 21-23 nucleotides that control the activity of various protein-coding genes through post-transcriptional repression. In this systematic review, we report the recent clinical evidence on the role of miRNAs as biomarkers for the prediction, prognosis, early detection, and risk stratification of SICH.

Methods: We conducted a systematic search of PubMed, PubMed Central, MEDLINE, and Embase databases and included only full-text peer-reviewed articles published in English.

Results: We included 10 studies comprising seven case-control studies, two cohort studies, and one cross-sectional study, among which we found 27 altered miRNAs, suggesting their role as biomarkers for the early detection of ICH. Additionally, the expression of 34 miRNAs was associated with poor prognosis of ICH; miR-126 and miR-23a-3p expression correlated with relative perihematomal edema (PHE) volume, and using a subset of 10 miRNA signatures had an accuracy of 100% in predicting hematoma in patients with ICH. Moreover, miR-4317 and miR-4325 profiling predicted the development of late seizures. Thirty-nine miRNAs were associated with the incidence of all types of strokes, while 10 miRNAs correlated with the predicted risk of stroke but were not specific to a stroke subtype. The altered miRNA signatures contributed to endothelial dysfunction, hematoma, and PHE through leukocyte activation, oxidative stress response, programmed cell death, smooth muscle cell proliferation, and apoptosis of cerebrovascular endothelial cells. The current data had limitations and gaps, especially the human studies, and there may have been selection bias in the prospective studies. There were also some limitations regarding the methods for obtaining miRNAs and identifying target RNAs specific to SICH pathology. Additionally, there may have been correlations between the outcomes and other factors, such as therapeutic interventions and ICH severity, the circulating miRNA profiles and gene expression profiles, and other pathological conditions and patients' age. Finally, the prediction and risk stratification of SICH could not be calculated separately from ischemic stroke.

Conclusions: Following our literature retrieval, we noted alterations in various miRNA signatures, suggesting their potential role as biomarkers for the early detection and differentiation of SICH. Indeed, miRNA expression was associated with a poor prognosis of SICH and correlated with the predicted risk of stroke but was not specific to a stroke subtype. Further studies are needed, especially on the therapeutic potential of miRNAs and their target RNAs in SICH.

Keywords: Biomarkers; Diagnosis; Hemorrhagic stroke; Intracerebral hemorrhages; MicroRNAs; Prediction; Prognosis; Risk stratification.