Neutrophil Extracellular Traps and Delayed Cerebral Ischemia in Aneurysmal Subarachnoid Hemorrhage

Abstract

IMPORTANCE: Myeloperoxidase (MPO)-DNA complexes, biomarkers of neutrophil extracellular traps (NETs), have been associated with arterial and venous thrombosis. Their role in aneurysmal subarachnoid hemorrhage (aSAH) is unknown. OBJECTIVES: To assess whether serum MPO-DNA complexes are present in patients with aSAH and whether they are associated with delayed cerebral ischemia (DCI). DESIGN, SETTING, AND PARTICIPANTS: Post-hoc analysis of a prospective, observational single-center study, with de novo serum biomarker measurements in consecutive patients with aSAH between July 2018 and September 2020, admitted to a tertiary care neuroscience ICU. MAIN OUTCOMES AND MEASURES: We analyzed serum obtained at admission and hospital day 4 for concentrations of MPO-DNA complexes. The primary outcome was DCI, defined as new infarction on brain CT. The secondary outcome was clinical vasospasm, a composite of clinical and transcranial Doppler parameters. We used Wilcoxon signed-rank-test to assess for differences between paired measures. RESULTS: Among 100 patients with spontaneous subarachnoid hemorrhage, mean age 59 years (sd ± 13 yr), 55% women, 78 had confirmed aSAH. Among these, 29 (37%) developed DCI. MPO-DNA complexes were detected in all samples. The median MPO-DNA level was 33 ng/mL (interquartile range [IQR], 18–43 ng/mL) at admission, and 22 ng/mL (IQR, 11–31 ng/mL) on day 4 (unpaired test; p = 0.015). We found a significant reduction in MPO-DNA levels from admission to day 4 in patients with DCI (paired test; p = 0.036) but not in those without DCI (p = 0.17). There was a similar reduction in MPO-DNA levels between admission and day 4 in patients with (p = 0.006) but not in those without clinical vasospasm (p = 0.47). CONCLUSIONS AND RELEVANCE: This is the first study to detect the NET biomarkers MPO-DNA complexes in peripheral serum of patients with aSAH and to associate them with DCI. A pronounced reduction in MPO-DNA levels might serve as an early marker of DCI. This diagnostic potential of MPO-DNA complexes and their role as potential therapeutic targets in aSAH should be explored further.

Neutrophil extracellular trap biomarkers in aneurysmal subarachnoid hemorrhage: early decline of DNase 1 activity associated with delayed cerebral ischemia

“…We conducted a post-hoc analysis with de novo investigation of myeloperoxidase (MPO)-DNA complexes, a biomarker of released NETs in circulation. Effectively, for the first time, it was demonstrated that MPO-DNA complex levels were significantly associated with DCI (8,9). These observations in context with the current literature incited us to further explore NET and NET-related biomarkers in the same cohort that are complementary to HMGB1 and MPO-DNA complexes.…”

Targeting Neutrophil Extracellular Traps for Stroke Prognosis: A Promising Path

“…Apart from that, Witsch et al showed that high concentrations of MPO-DNA complexes were present in all patients with aneurysmal SAH on admission regardless of the development of delayed cerebral ischemia (DCI) or clinical vasospasm. Additionally, increased NLR as a marker of post-SAH inflammation was consistently linked in different studies with DCI [ 42 ]. Finally, in autopsies of patients who died of spontaneous ICH, Puy et al found that the total number of neutrophils was increased in the area of the hematoma compared with the contralateral sections in control groups, in which no neutrophils were observed within the tissue.…”

“…On another note, in SAH patients, MPO-DNA levels seemed to decrease on day 4 in patients with DCI and patients with clinical vasospasm [ 42 ]. This finding also supports the abovementioned idea that more research is needed to assess the potential use of NETs as a potent biomarker to predict time of onset.…”

“…This finding also supports the abovementioned idea that more research is needed to assess the potential use of NETs as a potent biomarker to predict time of onset. However, high levels of MPO-DNA complexes were detected in all patients with aneurysmal SAH, independently of DCI and/or clinical vasospasm presented at admission [ 42 ], and H3cit levels were also higher in patients with aneurysmal SAH compared with healthy controls [ 21 ]. Inflammation and oxidative stress are speculated to be vital contributors to the pathological process of brain injury after stroke, and NET release many cytotoxic proteases and therefore induce endothelial cell damage and disrupt vascular homeostasis [ 36 ].…”

“…They suggested that NET formation within blood vessels and cerebral parenchyma in the peri-infarct cortical areas may impair revascularization and vascular remodeling after stroke and therefore be associated with higher NIHSS scores [ 32 ]. A significant positive correlation between plasma H3cit levels and clinical severity was demonstrated for patients suffering from aneurysmal SAH as well [ 42 ]. Another interesting finding in terms of post-stroke mortality risk comes from Cai et al, as patients who died at one-year clinical follow-up from all causes had significantly higher citH3 at stroke onset than survivors [ 3 ].…”