Biomarker Discovery in Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage

Abstract

Background: Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating problem. Overall, the mortality rate associated with aSAH is 32% to 67%, which makes it the most lethal type of hemorrhagic stroke. Once the aneurysm has been treated, cerebral vasospasm is the leading cause of morbidity and mortality associated with aSAH. Thus, ability to effectively prevent or treat cerebral vasospasm could result in significantly improved survival and quality of life for aSAH patients. Unfortunately, partly because of poor understanding of the mechanisms of vasospasm, current diagnosis and treatment can be inconsistent and/or ineffective. Current treatment methods include primarily medical therapy and endovascular methods. Alone, or in combination, these measures can be of benefit in some patients. However, they are not uniformly efficacious and, on an individual basis, they can present significant risks. These risks include stroke, cardiovascular compromise, and death. More effective diagnosis and treatment strategies could significantly improve patient outcomes after aSAH. Unfortunately, clinically reliable biomarker for cerebral vasospasm has yet to be identified. Biomarker discovery may facilitate earlier diagnosis of vasospasm and improved monitoring of the response to treatment. It may help in stratifying patients into categories of risk to develop vasospasm, which could subsequently guide therapy. Indeed, biomarker research may suggest "vasospasm phenotypes" that can be used to guide the most effective type of therapy for that particular patient. The purpose of this manuscript is to review the current cerebral vasospasm biomarker literature.

Methods: An extensive PubMed literature search was performed. We identified over 100 English language articles with key words cerebral vasospasm and biomarkers. Some of these articles and related references were used as the basis of this review. We focused on related human studies performed within the past 10 years.

Results: In this review, we focus on recent work identifying molecular markers of cerebral vasospasm following aSAH and the current understanding of the utility of these markers. We highlight novel approaches such as the use of cellular microparticles for the evaluation of cerebral vasospasm.

Conclusions: Although multiple molecules have been proposed, no single molecule has been shown to be a clinically reliable biomarker for cerebral vasospasm. This is not surprising based on the complex pathogenesis of cerebral vasospasm. Indeed, it is unlikely that a single biomarker will be clinically effective and reliable for predicting cerebral vasospasm. Instead, cerebral vasospasm may be best predicted by a panel of markers and the temporal progression of their relative levels after aSAH. Many such candidate molecules are reviewed herein and can be categorized as markers of cell damage, inflammation, changes in metabolism and vascular tone as well as microparticle-derived biomarkers. Among these, microparticle-derived biomarkers seem to be promising and lend themselves to further study. Biomarker discovery may facilitate earlier diagnosis of vasospasm and improved monitoring of the response to treatment. Ultimately, it may guide in the development of safer and more effective therapies for the most dreaded of aSAH complications.

Keywords: Cerebral aneurysm; biomarkers; cerebral vasospasm; microparticles; subarachnoid hemorrhage.