Role of Endothelin-1 in Human Aneurysmal Subarachnoid Hemorrhage: Associations with Vasospasm and Delayed Cerebral Ischemia

Abstract

Background Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the pathogenesis of vasospasm and delayed cerebral ischemia (DCI) in aneurysmal subarachnoid hemorrhage (aSAH) patients. The aim of this study was to investigate the relationship between cerebrospinal fluid (CSF) ET-1 levels and angiographic vasospasm and DCI. Methods Patients with aSAH were consented (n = 106). Cerebral vasospasm was determined by angiography. DCI was determined by transcranial Doppler (TCD) results and/or angiogram results with corresponding clinical deterioration. CSF ET-1 levels over 14 days after the initial insult was quantified by ELISA. ET-1 analysis included a group-based trajectory analysis and ET-1 exposure rate during 24, 48, and 72 h prior to, as well as 72 h post angiography, or clinical deterioration. Results Trajectory analysis revealed two distinct groups of subjects with 56% of patients in the low ET-1 trajectory group (mean at day 1 = 0.31 pg/ml; SE = 0.04; mean at day 14 = 0.41 pg/ml; SE = 0.15) and 44% of patients in the high ET-1 trajectory group (mean at day 1 = 0.65 pg/ml; SE = 0.08; mean at day 14 = 0.61 pg/ml; SE = 0.06). Furthermore, we observed that ET-1 exposure rate 72 h before angiography and clinical spasm was a significant predictor of both angiographic vasospasm and DCI, whereas, ET-1 exposure after angiography and clinical spasm was not associated with either angiographic vasospasm or DCI. Conclusion Based on these results we conclude that ET-1 concentrations are elevated in a sub-group of patients and that the acute (72 h prior to angiography and clinical neurological deterioration), but not chronic, elevations in CSF ET-1 concentrations are indicative of the pathogenic alterations of vasospasm and DCI in aSAH patients.

Soluble and Catalytically Active Endothelin Converting Enzyme-1 is Present in Cerebrospinal Fluid of Subarachnoid Hemorrhage Patients

“…Catalytically active ECE-1 in CSF can convert BigET-1 to the potent vasoconstrictor ET-1. Previous studies have demonstrated the presence of both BigET-1 and ET-1 in CSF of SAH subjects (6), and an association between ET-1 and cerebral vasospasm has previously been shown (7). In this light, our discovery of soluble ECE-1 in CSF of SAH subjects indicates that the production of ET-1 can in fact occur in the CSF space.…”

Interleukin-1&bgr; Increases Release of Endothelin-1 and Tumor Necrosis Factor as Well as Reactive Oxygen Species by Peripheral Leukocytes During Experimental Subarachnoid Hemorrhage

“…ET-1, a potent vasoconstrictor, is associated with both vasospasm resulting from SAH and delayed cerebral ischemia [48]. Elevated CSF levels of this cytokine have been correlated with pathologies observed after cerebral hemorrhage in humans [49] as well as in animal model [50].…”

A Phase I proof-of-concept and safety trial of sildenafil to treat cerebral vasospasm following subarachnoid hemorrhage

“…Endothelin-1, a potent cerebral vasoconstrictor, has been strongly implicated in early brain injury, CVS, and ultimately DCI following aneurysmal SAH. 3,29,36,37,39,46,48,[50][51][52][53]75,79,86 Studies evaluating endothelial function in erectile dysfunction and pulmonary hypertension have demonstrated that sildenafil substantially reduces endothelin-1 levels. 44,60,64,65 The development of platelet-induced microthrombi within the microvasculature has also been implicated in DCI, [20][21][22]63,70 and sildenafil has been shown to limit this prothrombotic cascade.…”