Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2)

Macdonald, R. Loch; Higashida, Randall T.; Keller, Emanuela; Mayer, Stephan A.; Molyneux, Andy; Raabe, Andreas; Vajkoczy, Peter; Wanke, Isabel; Bach, Doris; Frey, Aline; Marr, Angelina; Roux, Sébastiên; Kassell, Neal F.

doi:10.1016/s1474-4422(11)70108-9

Cited by 540 publications

(405 citation statements)

References 24 publications

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“…Despite successfully reducing angiographic vasospasm, long-term patient outcome was not affected by administration of the non-glucocorticoid 21-aminosteroid tirilazad 11 or the endothelin receptor antagonist clazosentan. 12 It may be that, beyond examining short-term preclinical outcomes (such as early brain injury and cerebral vasospasm), the successful translation of putative therapies would be predicted by evaluation of long-term neurobehavioral outcomes in preclinical models, 13 as recommended by the Stroke Therapy Academic Industry Roundtable criteria. 14 Experimental SAH research has thus sought to model long-term neurobehavioral outcomes and elucidate the mechanisms responsible.…”

Section: Introductionmentioning

confidence: 99%

Endovascular Perforation Subarachnoid Hemorrhage Fails to Cause Morris Water Maze Deficits in the Mouse

Holtzman

Friess

Hartman

et al. 2014

J Cereb Blood Flow Metab

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Cognitive dysfunction is the primary driver of poor long-term outcome in aneurysmal subarachnoid hemorrhage (SAH) survivors; modeling such deficits preclinically is thus key for mechanistic and translational investigation. Although rat SAH causes long-term deficits in learning and memory, it remains unknown whether similar deficits are seen in the mouse, a species particularly amenable to powerful, targeted genetic manipulation. We thus subjected mice to endovascular perforation SAH and assessed long-term cognitive outcome via the Morris water maze (MWM), the most commonly used metric for rodent neurocognition. No significant differences in MWM performance (by either of two protocols) were seen in SAH versus sham mice. Moreover, SAH caused negligible hippocampal CA1 injury. These results undercut the potential of commonly used methods (of SAH induction and assessment of long-term neurocognitive outcome) for use in targeted molecular studies of SAH-induced cognitive deficits in the mouse.

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Section: Introductionmentioning

confidence: 99%

Endovascular Perforation Subarachnoid Hemorrhage Fails to Cause Morris Water Maze Deficits in the Mouse

Holtzman

Friess

Hartman

et al. 2014

J Cereb Blood Flow Metab

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“…Recently, this paradigm has been challenged, leading to a reevaluation of the causal relationship between angiographically defined vasospasm of surface conduit arteries and SAH-induced morbidity and mortality (5)(6)(7). Supporting this change in sentiment, clinical trials have found that the endothelin-1A receptor antagonist clazosentan significantly decreased the incidence of large-artery vasospasm but failed to improve outcome in SAH patients (8,9). Additional mechanisms that may contribute to SAH-induced DINDs include early brain injury, inflammation, cortical spreading depression, and focal cortical infarcts arising from perfusion deficiencies within the microcirculation (5,6,10,11).…”

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confidence: 99%

Inversion of neurovascular coupling by subarachnoid blood depends on large-conductance Ca ²⁺ -activated K ⁺ (BK) channels

Koide

Bonev

Nelson

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

101

108

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The cellular events that cause ischemic neurological damage following aneurysmal subarachnoid hemorrhage (SAH) have remained elusive. We report that subarachnoid blood profoundly impacts communication within the neurovascular unit-neurons, astrocytes, and arterioles-causing inversion of neurovascular coupling. Elevation of astrocytic endfoot Ca 2+ to ∼400 nM by neuronal stimulation or to ∼300 nM by Ca 2+ uncaging dilated parenchymal arterioles in control brain slices but caused vasoconstriction in post-SAH brain slices. Inhibition of K + efflux via astrocytic endfoot large-conductance Ca 2+ -activated K + (BK) channels prevented both neurally evoked vasodilation (control) and vasoconstriction (SAH

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“…[6][7][8] However, the stenosis of the spastic artery alone cannot fully explain the subsequent development of DCI, as not all patients with CVS, detected either radiologically or with transcranial Doppler (TCD), develop DCI. [8][9][10] For this reason, assessment of changes in the cerebral microvasculature distal to spastic vessels may be important. However, previous studies have yielded conflicting results.…”

Section: Introductionmentioning

confidence: 99%

Cerebral Vasospasm Affects Arterial Critical Closing Pressure

Varsos

Budohoski

Czosnyka

et al. 2014

J Cereb Blood Flow Metab

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The effect of cerebral vasospasm (CVS) after aneurysmal subarachnoid hemorrhage (SAH) on critical closing pressure (CrCP) has not been fully delineated. Using cerebral impedance methodology, we sought to assess the behavior of CrCP during CVS. As CrCP expresses the sum of intracranial pressure (ICP) and vascular wall tension, we also explored its role in reflecting changes in vascular tone occurring in small vessels distal to spasm. This retrospective analysis was performed using recordings from 52 patients, diagnosed with CVS through transcranial Doppler measurements. Critical closing pressure was calculated noninvasively using arterial blood pressure and blood flow velocity. Outcome was assessed at both discharge and 3 months after ictus with the Glasgow Outcome Scale. The onset of CVS caused significant decreases in CrCP (P = 0.025), without any observed significant changes in ICP (P = 0.134). Vasospasm induced asymmetry, with CrCP ipsilateral to CVS becoming significantly lower than contralateral (P = 0.025). Unfavorable outcomes were associated with a significantly lower CrCP after the onset of CVS (discharge: P = 0.014; 3 months after SAH: P = 0.020). Critical closing pressure is reduced in the presence of CVS in both temporal and spatial assessments. As ICP remained unchanged during CVS, reduced CrCP most probably reflects a lower wall tension in dilated small vessels distal to spasm.

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Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2)

Cited by 540 publications

References 24 publications

Endovascular Perforation Subarachnoid Hemorrhage Fails to Cause Morris Water Maze Deficits in the Mouse

Endovascular Perforation Subarachnoid Hemorrhage Fails to Cause Morris Water Maze Deficits in the Mouse

Inversion of neurovascular coupling by subarachnoid blood depends on large-conductance Ca ²⁺ -activated K ⁺ (BK) channels

Cerebral Vasospasm Affects Arterial Critical Closing Pressure

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Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2)

Cited by 540 publications

References 24 publications

Endovascular Perforation Subarachnoid Hemorrhage Fails to Cause Morris Water Maze Deficits in the Mouse

Endovascular Perforation Subarachnoid Hemorrhage Fails to Cause Morris Water Maze Deficits in the Mouse

Inversion of neurovascular coupling by subarachnoid blood depends on large-conductance Ca 2+ -activated K + (BK) channels

Cerebral Vasospasm Affects Arterial Critical Closing Pressure

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Inversion of neurovascular coupling by subarachnoid blood depends on large-conductance Ca ²⁺ -activated K ⁺ (BK) channels