To identify plasma biomarkers within the Sulfonylurea-receptor-1(SUR1)—transient-receptor-potential-cation-channel-M-member-4 (TRPM4) pathway associated with secondary brain injury after aneurysmal-subarachnoid hemorrhage (aSAH). 

The SUR1-TRPM4 pathway has been mechanistically implicated in secondary injuries (cerebral-edema, vasospasm, and delayed cerebral ischemia (DCI)) post-aSAH; representing a promising therapeutic target. Yet, no clinically available biomarkers currently exist to predict/monitor these secondary injuries. Plasma, a minimally-invasive, low-risk, clinically-practical biofluid, is a valuable platform for biomarker translation.  

In a prospectively enrolled cohort  (84 plasma samples: 69 aSAH, 15 uninjured-control, multiple timepoints/patient), we quantified 175 proteins identified in the SUR1-TRPM4 pathway (SomaScan). Outcomes included cerebral-edema (subarachnoid-hemorrhage-early-brain-edema (SEBES) score on CT), vasospasm (conventional angiography), DCI (CT/MRI), and discharge disposition. An initial screen of differential expression was assessed via t-tests (Benjamini-Hochberg correction). Multivariate integrative sparse partial least squares identified the most discriminative proteins and confirmed robustness. Longitudinal associations were tested using linear mixed-models (generalized-estimating-equations), controlling age, Hunt-Hess, sex, modified-Fisher. 

Thirty-one proteins were elevated post-aSAH vs controls (all-p_adj=0.049-0.005); ≥20% increase was seen in eighteen proteins including APOE isoforms and others that were detectable at markedly higher levels in cerebrospinal fluid in a separate study (IL6, HMOX1, IL2, FOXO1). Sixteen proteins varied over time, with six increasing between 24h-96 post aSAH (all-p_adj=0.049-0.0002). Twenty-six proteins were associated with cerebral edema, of which four were also associated with vasospasm; overlapping proteins were mediators of inflammation and blood-brain-barrier (BBB) breakdown (IL1b, MMP9, AQP4), others were novel targets (S100A14, ADGRF5).  Twenty-four proteins were associated with DCI- distinct from vasospasm profiles. Seven proteins were associated with ≥1.5% increased odds of death at discharge per-unit increase(all-p_adj<10-6). SHC-SH2 and ITGB6 were protective, conferring 32% and 42% reduced odds of death respectively.

SUR1-TRPM4-linked plasma protein signatures are quantifiable post-aSAH and associated with secondary injury. Overlap with CSF markers (reported elsewhere) identifies potentially high-yield targets for minimally-invasive biomarker development.