Plasma Proteins in the SUR1–TRPM4 Pathway are Associated with Secondary Injury and Outcome after Aneurysmal Subarachnoid Hemorrhage
Shreya Satheesh1, Aurelia Cors2, Aditya Kumar3, Anupama Rani3, Diana Sanchez3, Nasathapot Namphol3, Margaux Miller4, Erin McNally3, Raemier Javelosa3, Jane Hwang3, Kaitlyn Hebig3, Sirin Gandhi3, Adam Eberle5, Joshua Catapano6, Semeon Afework3, Thomas Donovan7, Ethan Gaskin7, Felipe Albuquerque3, Andrew Ducruet3, Ashutosh Jadhav3, Michael Lawton3, Patrick Kochanek7, Dhivyaa Rajasundaram7, Ruchira Jha3
1Arizona State University, 2Yale University, 3Barrow Neurological Institute, 4Temple University, 5Mount Sinai, 6University of Pennsylvania, 7University of Pittsburgh
Objective:
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).
Background:
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.
Design/Methods:
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.
Results:
Thirty-one proteins were elevated post-aSAH vs controls (all-padj=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-padj=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-padj<10-6). SHC-SH2 and ITGB6 were protective, conferring 32% and 42% reduced odds of death respectively.
Conclusions:
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.
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