Soluble ST2 links inflammation to outcome after subarachnoid hemorrhage

Abstract

Objective: To investigate whether soluble growth stimulation expressed gene 2 (sST2), a prognostic marker in cardiovascular and inflammatory disorders, is associated with neurological injury after aneurysmal subarachnoid hemorrhage (SAH). Methods: We studied SAH patients from 2 independent cohorts. Outcome assessments included functional status at 90 days using the modified Rankin Scale (mRS), mortality, and delayed cerebral ischemia (DCI). The relationships between sST2 plasma level and outcome measures were assessed in both cross-sectional and longitudinal analysis. Primary blood mononuclear cells from SAH patients and elective aneurysm controls were analyzed by multiparameter flow cytometry. Results: In the discovery cohort, sST2 predicted 90-day mRS 3-6 (C index = 0.724, p < 0.001) and mortality in Kaplan-Meier analysis (p < 0.001). The association with functional status was independent of age, sex, World Federation of Neurosurgical Societies score, modified Fisher score, treatment modality, and cardiac comorbidities (adjusted odds ratio = 2.28, 95% confidence interval = 1.04-5.00, p = 0.039). Higher sST2 concentration was observed in those patients with DCI (90.8 vs 53.7ng/ml, p = 0.003). These associations were confirmed in a replication cohort. In patients with high sST2, flow cytometry identified decreased expression of CD14 (4.27 × 10 5 AE 2,950 arbitrary unit (AU) vs 5.64 × 10 5 AE 1,290 AU, p < 0.001), and increased expression of CD16 (39,960 AE 272 AU vs 34,869 AE 183 AU, p < 0.001). Interpretation: Plasma sST2 predicts DCI, functional outcome, and mortality after SAH, independent of clinical and radiographic markers. Elevated sST2 is also associated with changes in CD14 + CD16 + monocytes.

The Role of the Blood Neutrophil-to-Lymphocyte Ratio in Aneurysmal Subarachnoid Hemorrhage

“…Severe subarachnoid hemorrhage is associated with the strong early inflammatory response ( 88 ), and the most direct and easily observed result is the change in peripheral inflammatory biomarkers, such as the neutrophil and lymphocyte counts ( 89 , 90 ). In general, an increase in neutrophils in peripheral blood is a manifestation of inflammation in the CNS and may be related to the development of extracerebral organ immune dysfunction.…”

Mast Cells Mediate Inflammatory Injury and Aggravate Neurological Impairment in Experimental Subarachnoid Hemorrhage Through Microglial PAR-2 Pathway

“…Previous studies indicated that inflammatory response peaks at 24–48 h post-bleeding. And the elevated neuroinflammation is associated with higher clinical severity, delayed cerebral ischemia, mortality, and functional outcome after SAH ( Ahn et al, 2019 ; Bevers et al, 2019 ). In addition, recent studies suggested that inhibition of Enhancer of Zeste Homolog 2 (EZH2) or thromboxane-prostaglandin (TP) receptors could afford a robust neuroprotective effect against SAH via inhibiting neuroinflammation in a rat model of SAH ( Lagier et al, 2019 ; Luo et al, 2020 ).…”

Cerebral Cavernous Malformation: Immune and Inflammatory Perspectives

“…The relationship between hemorrhagic events and inflammatory responses has been well described in multiple cerebrovascular anomalies, including aneurysm ( 95 , 96 ), cerebral arteriovenous malformation ( 97 ), cerebral amyloid angiopathy ( 98 , 99 ), and ischemic cerebrovascular disorders ( 100 , 101 ). Notably, acute brain hemorrhages may not have an opportunity to lead a similar milieu with the longstanding deposition of blood products, because it would be absorbed over a normal length of time.…”