The role of venous impairment in subarachnoid hemorrhage pathophysiology

ABSTRACT Aneurysmal subarachnoid hemorrhage (SAH) is a severe type of hemorrhagic stroke with overall mortality rate of 51% and long-term morbidity among more than a third of survivors [1-3, 26, 27]. Large artery vasospasm has been the focus of SAH research for past 50 years but preventing vasospasm has not always translated into improved patient outcomes. The cerebral venous circulation is critical since 70% of the cerebral blood volume, which constitutes approximately 6% of brain volume under normal conditions, is located in venous vascular bed [15]. Variations in cerebral venous drainage pattern, venous obstruction, stenosis of internal jugular veins, and venous sinus morphological anomalies are frequently encountered which can have direct implications for SAH outcomes. A cerebral angiography series study showed over 50% of those aneurysm cases had both asymmetric dural sinuses and SAH [10]. Furthermore, patients with cerebral venous thrombosis can present as SAH [22, 23]. However, the role of cerebral venous circulation in SAH pathophysiology has not been explored. This proposal will elucidate the role of cerebral venous impariment in SAH pathology using a new mouse model of SAH with ipsilateral jugular vein occlusion. We hypothesize that impaired cerebral venous drainage will lead to cerebrospinal fluid (CSF) outflow obstruction, increase cerebral venous sinus pressure, and promote CSF hypersecretion which will cause an acute and fatal elevation in intracranial pressure (ICP) following SAH. We will develop and characterize a new mouse model of SAH with ipsilateral jugular venous outflow obstruction and determine the outcomes after SAH. Next, we will elucidate potential mechanisms how ipsilateral venous obstruction increases ICP after SAH and explore potential strategies to manage increased ICP after SAH with ipsilateral jugular venous occlusion in the new mouse model. Overall, this proposal will provide a new perspective on the role of cerebral venous system in SAH pathophysiology which can potentially discover new therapeutic strategies for SAH patients.