Plasma Periostin and Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

Abstract

Delayed cerebral ischemia (DCI) is a serious complication of aneurysmal subarachnoid hemorrhage (SAH). Matricellular protein periostin (POSTN) has been found to be upregulated and linked with early brain injury after experimental SAH. The aim of the present study was to investigate the relationship between plasma POSTN levels and various clinical factors including serum levels of C-reactive protein (CRP), an inflammatory marker, in 109 consecutive SAH patients whose POSTN levels were measured at days 1-12 after aneurysmal obliteration. DCI developed in 16 patients associated with higher incidence of angiographic vasospasm, cerebral infarction, and 90-day worse outcomes. POSTN levels peaked at days 4-6 before DCI development. Cerebrospinal fluid (CSF) drainage was associated with reduced POSTN levels, but did not influence CRP levels. There was no correlation between POSTN levels and other treatments or CRP levels. To predict DCI development, receiver-operating characteristic curves indicated that the most reasonable cutoff POSTN levels were obtained at days 1-3 in patients without CSF drainage (80.5 ng/ml; specificity, 77.6%; sensitivity, 85.7%). Multivariate analyses using variables obtained by day 3 revealed that POSTN level was an independent predictor of DCI. POSTN levels over the cutoff value were associated with higher incidence of DCI, but not angiographic vasospasm. This study shows for the first time that CSF drainage may reduce plasma POSTN levels, and that POSTN levels may increase prior to the development of DCI with and without vasospasm irrespective of systemic inflammatory reactions in clinical settings. These findings suggest POSTN as a new therapeutic molecular target against post-SAH DCI.

The Role of Periostin in Brain Injury Caused by Subarachnoid Hemorrhage

“…In clinical settings, Luo et al measured the serum periostin levels at admission and reported that higher levels of serum periostin were associated with a poorer clinical grade at admission, higher frequency of development of DCI, and worse neurological outcomes in the aSAH patients [66]. In a recent study conducted by our research group, plasma periostin levels were chronologically measured 4 times during the period between the post-operative or postinterventional Day 1 and post-aSAH Day 12; the plasma periostin levels were observed to peak at Day 4-6 after onset, and later, development of DCI was observed [39]. Although periostin is a kind of inflammatory marker [28], the study revealed that the plasma periostin levels exhibited no correlation with the serum levels of a systemic inflammatory marker named C-reactive protein [39].…”

“…Although periostin is a kind of inflammatory marker [28], the study revealed that the plasma periostin levels exhibited no correlation with the serum levels of a systemic inflammatory marker named C-reactive protein [39]. However, cerebrospinal fluid drainage was observed to significantly lower the plasma periostin levels at all time points of measurement, possibly because the drainage of cerebrospinal fluid removed periostin before the latter moved from the brain extracellular fluid or the cerebrospinal fluid to peripheral blood [39]. Multivariate logistic regression analyses conducted using all the clinical variables by Day 3 post-aSAH demonstrated that the plasma periostin levels at Days 1-3 post-aSAH (post-operative or post-interventional Day 1) served as an independent predictor of DCI, irrespective of the subsequent development of cerebral vasospasm [39].…”

“…However, cerebrospinal fluid drainage was observed to significantly lower the plasma periostin levels at all time points of measurement, possibly because the drainage of cerebrospinal fluid removed periostin before the latter moved from the brain extracellular fluid or the cerebrospinal fluid to peripheral blood [39]. Multivariate logistic regression analyses conducted using all the clinical variables by Day 3 post-aSAH demonstrated that the plasma periostin levels at Days 1-3 post-aSAH (post-operative or post-interventional Day 1) served as an independent predictor of DCI, irrespective of the subsequent development of cerebral vasospasm [39]. At present, the commercially available enzyme-linked immunosorbent assay kits are able to measure the concentration of four well-known splicing variants of periostin (a full-length variant containing all 9 exons; a variant lacking exon 17; a variant lacking exon 21; and a variant lacking exons 17 and 21) together, although a separate measurement is not possible with these kits yet [27].…”

“…In a recent study conducted by our research group, plasma periostin levels were chronologically measured 4 times during the period between the post-operative or postinterventional Day 1 and post-aSAH Day 12; the plasma periostin levels were observed to peak at Day 4-6 after onset, and later, development of DCI was observed [39]. Although periostin is a kind of inflammatory marker [28], the study revealed that the plasma periostin levels exhibited no correlation with the serum levels of a systemic inflammatory marker named C-reactive protein [39]. However, cerebrospinal fluid drainage was observed to significantly lower the plasma periostin levels at all time points of measurement, possibly because the drainage of cerebrospinal fluid removed periostin before the latter moved from the brain extracellular fluid or the cerebrospinal fluid to peripheral blood [39].…”

“…Izuhara et al reported that ILs-4 and ILs-13 were able to activate the NF-κB pathway in the fibroblasts and promote periostin expression [28]. As NF-κB is expressed extensively along with multiple inflammatory cytokines in aSAH [38], it is compatible that periostin is upregulated with the NF-κB activation in aSAH as in other pathologies [2,39]. In order to conduct the mechanisms underlying the fibrotic diseases with inflammation, the cross-talk between periostin and TGF-β or the pro-inflammatory cytokines may be important [28].…”