PHE, as a quantifiable marker of secondary brain injury after ICH, is involved with a series of complicated processes. To our knowledge, a recent systematic review concluded the growth characteristics and relevant underlying mechanism of ICH related PHE. In brief, PHE occurrence and progression are related to thrombin activation, inflammatory response, blood–brain barrier (BBB) dysfunction, and hemoglobin cytotoxicity after ICH. Preclinical evidence demonstrates that different pathophysiologic mechanisms dominate the development of PHE at different stages of ICH. In the initial stage of PHE, the ionic edema driven by the cytotoxic edema dominates the first stage of PHE. The development of cytotoxic edema involves the Sur1-Trpm4 channel and Na-K-Cl cotransporter 1. Subsequently, the vasogenic edema induced by the inflammatory immune response dominates the second stage of PHE, which is characterized by BBB dysfunction. This process involves numerous molecules. In the neuroinflammation immune response, inflammatory cell chemotaxis, cytokine and chemokine release destroy the tight junctions between vascular endothelial cells and increase vascular permeability, simultaneously upregulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9). And, the third stage of PHE is mainly a delayed stage of vasogenic edema induced by erythrocyte lysis[31]. Based on the mentioned theoretical basis, our study aims to research the relevance between serum Sur1, Trpm4, MMP-9 concentrations and ICH related PHE.
Previous reports found serum Sur1 levels and cerebrospinal fluid(CSF) Sur1 levels may be related to traumatic severity and clinic prognosis of patients with traumatic brain injury[32-34]. An article involves serum Sur1 levels may be associated with functional outcome of patients with aneurysmal subarachnoid hemorrhage[26]. These data have indicated that Sur1 may be a potential prognostic biomarker of diseases with acute brain injury. Another two clinical trials involve sulfonylureas block the Sur1-Trpm4 channel and decrease PHE after ICH[25, 35]. These results have demonstrated that serum Sur1 levels may be correlated with PHE after ICH and could be inhibited by sulfonylureas.
Our study implicated the dynamic concentration changes of MMP-9, Sur1 and Trpm4 in blood after spontaneous ICH. The main findings were as follows: (1) Overexpression of these molecules could be measured in blood at different time points after ICH ictus, roughly single peak curve. (2) Sur1 and Trpm4 mean concentrations reached their peak at 3 days and peak MMP-9 mean concentrations can be detected at 5 days; (3) Peak Sur1 levels could be found to be correlated to neuroimaging characteristics and function outcome of day 90. (4) Peak Sur1 level was an independent predictor of day 90 outcome in ICH patients. Each milliliter of additional peak. Sur1 levels increased the absolute risk for a poor outcome by 1.5%.
Sur1, encoded byABCC8, is a member of the adenosine triphosphate (ATP)-binding cassette (ABC) protein superfamily. Sur1 combines with Trpm4 to form the Sur1-Trpm4 channel (previously Sur1-regulated NCCa-ATP channels). This channel opening will lead to influx of monovalent cations, resulting in depolarization of the cell, cytotoxic edema, blebbing and oncotic cell death. Generally, SUR-1 is not expressed in the normal brain tissues, but is transcriptionally upregulated after various forms of CNS injuries including ischemic stroke, traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage, spinal cord injury (SCI). Sur1-Trpm4 expression and contribution to cerebral edema and secondary injury has been demonstrated across several types of CNS injury in past studies. Simultaneously, Genetic silencing or sulfonylureas inhibition of Sur1-Trpm4 channel decreased cerebral edema and hemorrhage progression in multiple preclinical models, which also indirectly proves the above view[20, 36]. In conclusion, Sur1-Trpm4 channel may be as a potential therapeutic target of CNS injury.
There have been 2 clinical studies involving Sur1 concentrations in CSF of humans with TBI until now. And one report investigating Sur1 concentrations in serum. One study included 28 patients with severe TBI and 15 controls with normal pressure hydrocephalus demonstrated that elevated Sur1 levels in CSF after TBI were associated with CT-edema and preceded peak intracranial pressure, as well as Sur1 trajectories between 48 and 72 h were related with outcome indicated by Glasgow outcome score (GOS) at 3 months after trauma[33]. Another study enrolled 16 pediatric patients with severe TBI, Sur1 concentrations in CSF were associated with increased intracranial pressure over seven days and worse extended GOS score over the initial year after injury[37]. However, the two studies did not conduct multivariate analysis due to insufficient sample size. Also, an epidemiological analysis of patients with aneurysmal subarachnoid hemorrhage suggested that serum Sur1 levels were highly correlate with World Federation of Neurosurgical Societies score and GOS score at 14 days after stroke[26]. The same problem as previous studies, no multivariate analyses were used. Furthermore, a study involved 138 patients with moderate to severe TBI and 100 healthy controls, by utilizing multivariate analyses, rising serum Sur1 concentrations are highly correlated with traumatic severity and are independently associated with poor prognosis reflected by GOS score at 3 months after head trauma[34]. There have been two clinical studies involving sulfonylureas inhibition of SUR1-TRPM4 channel decrease PHE after ICH. One study involved 21 ICH patients with type 2 diabetes mellitus prescribed sulfonylureas and 42 ICH non-sulfonylurea matched controls with diabetes mellitus, Final result display that sulfonylurea use predicted lower ICH and PHE volumes, lower relative PHE, and improved discharge disposition[25]. Another study investigated 37 ICH patients with Sulfonylurea pretreatment and 193 ICH patients without Sulfonylurea pretreatment, Sulfonylurea pretreatment may be an independent predictor for smaller initial HV, milder admission ICH severity, and improved functional outcome indicated by modified Rankin Scale score (mRS) at discharge in diabetic patients with acute ICH[35]. These two clinical reports indicated that inhibition of Sur1-Trpm4 channel contributed to good prognosis. Our study enrolled 51 patients and 51 healthy controls and used multivariate analyses to assess relationship between serum Sur1 levels and traumatic severity in addition to prognosis at 3 months evaluated by MRS score at 90 days after ICH; moreover, this biomarker displayed similar predictive capability, as compared to MMP-9, hematoma volume and ICH score. Our data demonstrated that serum Sur1 concentrations, in an independent correlation with ICH severity assessed by hematoma volume and MMP-9, independently predicted a poor outcome (defined as MRS score 0–3) at 3 months after ICH. Moreover, in this study, serum Sur1 concentrations distinct differed between patients with the development of a poor 3-month outcome and those presenting with a good outcome at AUC of 0.785. Using maximum Youden index, serum Sur1 concentrations >13.28 ng/ml distinguished the risk of a poor outcome with medium-high sensitivity and specificity values. In summary, serum Sur1 may represent a potential prognostic biomarker of acute ICH.
Limitation
Several limitations should be noted in our study. As a retrospective study with strict inclusion criteria, it is possible that cases and controls are not representative of the broader populations of patients with ICH and our findings occurred by chance. Second, because we have included mostly patient with mild to medium ICH, excluded severe patients with ICH, hematoma volume is generally small. Therefore, such conclusions whether can be extended to patients with larger hematoma volume need further studied. Third, male patients occupy a large proportion in this study, we still need more data to confirm whether gender has an impact on outcomes.