# Elevated acute-phase plasma levels of S100A12 [EN-RAGE] are associated with vascular recurrence after ischemic stroke

## TL;DR

This study finds that high levels of the protein S100A12 in blood are linked to a higher risk of recurring vascular events after an ischemic stroke.

## Contribution

S100A12 is identified as a novel biomarker for vascular recurrence after ischemic stroke.

## Key findings

- Elevated S100A12 levels are independently associated with recurrent MACE and stroke.
- The association of S100A12 with vascular recurrence was replicated in a second cohort.
- Subtype-specific protein associations with MACE were identified in exploratory analyses.

## Abstract

Despite modern secondary prevention the risk of recurrent vascular events in ischemic stroke remains substantial, and high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) are associated with vascular recurrence. This study aims to investigate whether other proteins in the inflammatory cascade could serve as better predictive biomarkers.

The discovery cohort comprised 559 ischemic stroke cases from SAHLSIS (age 18–69, median 58 years) with a median follow-up of 14.7 years. Acute-phase plasma levels of 65 inflammation-related proteins were assessed using the Olink Inflammation panel. Replication was sought using 502 cases from SAHLSIS2 (age 18–98, median 68 years) with a median follow-up of 3.6 years. Associations between proteins and recurrent major adverse cardiovascular events (MACE) and recurrent stroke were explored with Cox regression. For MACE in SAHLSIS, exploratory analyses stratified by etiologic subtype were performed. Analyses were adjusted for vascular risk factors and statin status.

In SAHLSIS, S100A12 was independently associated with recurrent MACE (adjusted hazard ratio (HR), 1.27 [95% confidence interval 1.10–1.45] per doubling of protein level) and stroke (adjusted HR 1.21 [1.01–1.45]). In SAHLSIS2, the associations for S100A12 replicated (adjusted HR, recurrent MACE 1.25 [1.06–1.48] and stroke 1.35 [1.10–1.66]). Results from the exploratory analyses identified several proteins displaying subtype-specific associations.

We identified S100A12 as a potential novel blood biomarker of vascular recurrence after ischemic stroke, and the results indicate that there are subtype-specific protein associations to recurrent MACE warranting further investigation.

Graphical Abstract