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Calcium and Potassium Channels in Experimental Subarachnoid Hemorrhage and Transient Global Ischemia  [PDF]
Marcel A. Kamp,Maxine Dibué,Toni Schneider,Hans-Jakob Steiger,Daniel H?nggi
Stroke Research and Treatment , 2012, DOI: 10.1155/2012/382146
Abstract: Healthy cerebrovascular myocytes express members of several different ion channel families which regulate resting membrane potential, vascular diameter, and vascular tone and are involved in cerebral autoregulation. In animal models, in response to subarachnoid blood, a dynamic transition of ion channel expression and function is initiated, with acute and long-term effects differing from each other. Initial hypoperfusion after exposure of cerebral vessels to oxyhemoglobin correlates with a suppression of voltage-gated potassium channel activity, whereas delayed cerebral vasospasm involves changes in other potassium channel and voltage-gated calcium channels expression and function. Furthermore, expression patterns and function of ion channels appear to differ between main and small peripheral vessels, which may be key in understanding mechanisms behind subarachnoid hemorrhage-induced vasospasm. Here, changes in calcium and potassium channel expression and function in animal models of subarachnoid hemorrhage and transient global ischemia are systematically reviewed and their clinical significance discussed. 1. Introduction Despite current treatment options, delayed cerebral ischemia following aneurismal subarachnoid hemorrhage (SAH) is still associated with a high morbidity and mortality [1]. The narrowing of cerebral blood vessels by vasospasm represents the main cause of delayed cerebral ischemia [2]. Because vasospastic smooth muscle cells are known to be depolarized compared to controls [3, 4], the expression and function of ion channels in these cells after SAH are of great interest. Furthermore, the inhibitor of L-type calcium channels nimodipine remains gold standard in treatment and prophylaxis of vasospasm after SAH. However, recent studies have revealed that several ion channels of different subfamilies are impacted by SAH and may contribute to delayed vasospasm. The goal of the present analysis is to review ion channel expression and function in healthy cerebral blood vessels as well as after SAH. 2. Ion Channels Healthy Cerebral Vessels 2.1. Expression and Function of Potassium Channels in Healthy Cerebral Vessels Membrane potential of cerebrovascular smooth muscle cells and thus dilation and constriction of cerebral arteries are directly dependent on potassium conductance [5, 6]. Members of four potassium superfamilies have been shown to be expressed in smooth muscle cells of healthy cerebral vessels: inwardly rectifying (Kir), ATP-dependent-(KATP), voltage-gated ( ), and large-conductance calcium-activated (BK) potassium channels. Kir2.1
Neurological and neurobehavioral assessment of experimental subarachnoid hemorrhage
Hyojin Jeon, Jinglu Ai, Mohamed Sabri, Asma Tariq, Xueyuan Shang, Gang Chen, R Loch Macdonald
BMC Neuroscience , 2009, DOI: 10.1186/1471-2202-10-103
Abstract: Mortality and morbidity from aneurysmal subarachnoid hemorrhage (SAH) have decreased with improvements in surgery, pharmacological treatment and intensive care. The overall outcome, however, remains relatively poor [1,2]. Management of SAH includes early obliteration of the ruptured aneurysm to prevent rebleeding, prevention of secondary brain injury from such things as decreased cerebral perfusion and prevention and treatment of delayed neurological deterioration secondary to cerebral vasospasm. The case fatality rate is approximately 50% and 30% of survivors remain dependent on others, mainly due to the persistent cognitive impairment rather than focal neurological deficits [3].Although the mechanisms underlying the cognitive deficits have not been well studied, they have nevertheless been attributed to ischemic brain injury occurring either during the initial hemorrhage or as a consequence of macro- and microvascular dysfunction and delayed ischemic neurological deterioration (Figure 1) [1]. Other mechanisms, including delayed neuronal death and cortical spreading depression have been suggested [4,5]. These processes may lead to large-artery territory infarction, smaller cortical laminar infarcts or possibly other types of selective neuronal death or perhaps even dysfunction in the absence of detectable death [6].Much work on SAH has focused on cerebral vasospasm. This is based on the assumption that severe vasospasm can reduce cerebral blood flow, cause brain ischemia and infarction and contribute to poor outcome [7]. For such studies, an acceptable dependent variable would be angiographic arterial diameter. This might not detect treatment toxicity, however. Considering the fact that the other proposed mechanisms do not necessarily cause focal cerebral infarctions, how to assess outcome is a problem. Clinically, neurobehavioral testing could be used and generally is done 3 to 6 months post-SAH.Animal studies have often relied on histological assessment of neuron
CSF and Serum Biomarkers Focusing on Cerebral Vasospasm and Ischemia after Subarachnoid Hemorrhage  [PDF]
Carla S. Jung,Bettina Lange,Michael Zimmermann,Volker Seifert
Stroke Research and Treatment , 2013, DOI: 10.1155/2013/560305
Abstract: Delayed cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) remain severe complications after subarachnoid hemorrhage (SAH). Although focal changes in cerebral metabolism indicating ischemia are detectable by microdialysis, routinely used biomarkers are missing. We therefore sought to evaluate a panel of possible global markers in serum and cerebrospinal fluid (CSF) of patients after SAH. CSF and serum of SAH patients were analyzed retrospectively. In CSF, levels of inhibitory, excitatory, and structural amino acids were detected by high-performance liquid chromatography (HPLC). In serum, neuron-specific enolase (NSE) and S100B level were measured and examined in conjunction with CVS and DCI. CVS was detected by arteriography, and ischemic lesions were assessed by computed tomography (CT) scans. All CSF amino acids were altered after SAH. CSF glutamate, glutamine, glycine, and histidine were significantly correlated with arteriographic CVS. CSF glutamate and serum S100B were significantly correlated with ischemic events after SAH; however, NSE did not correlate neither with ischemia nor with vasospasm. Glutamate, glutamine, glycine, and histidine might be used in CSF as markers for CVS. Glutamate also indicates ischemia. Serum S100B, but not NSE, is a suitable marker for ischemia. These results need to be validated in larger prospective cohorts. 1. Introduction Besides acute brain injury [1], one-third of patients suffering from subarachnoid hemorrhage (SAH) develop secondary brain injury [2]. This secondary brain injury leading to the majority of morbidity and mortality after SAH seems to be due to delayed cerebral vasospasm (CVS), which results in delayed cerebral ischemia (DCI) [3]. There are a number of other causes of cerebral ischemia other than CVS after SAH [4], which may manifest clinically as delayed ischemic neurological deficits (DINDs). CVS has been associated with DIND and DCI and was described for a long time as the underlying pathophysiology [5–8]. However, recent studies showed that ameliorating CVS is only partially effective in preventing DCI [9]. This might be explained by multifactorial mechanisms underlying DCI and the development of secondary brain injury. It further implies SAH and biomarker research aiming at a more comprehensive detection of secondary events after SAH; that one should not focus solely on CVS, but rather on evaluating CVS and DCI. Although extensive research has been conducted over the last decades on monitoring tissue biochemistry in the injured brain and some studies have identified predictors of CVS
Pharmacological treatment of delayed cerebral ischemia and vasospasm in subarachnoid hemorrhage
Diego Castanares-Zapatero, Philippe Hantson
Annals of Intensive Care , 2011, DOI: 10.1186/2110-5820-1-12
Abstract: Delayed cerebral ischemia (DCI) is a common and serious complication following subarachnoid hemorrhage (SAH) after ruptured cerebral aneurismal [1,2]. Although this complication is at times reversible, it may develop into a cerebral infarction [3]. DCI occurs in approximately 20% to 40% [4] of patients and is associated with increased mortality and poor prognosis [5,6]. It is usually caused by a vasospasm [7], which, although preventable, remains a major cause of poor neurological outcome and increased mortality in the course of SAH [4-6].Vasospasm is defined as a reversible narrowing of the subarachnoid arteries occurring between the third to fifth and fifteenth day after the hemorrhage, with a peak at the tenth day. It is observed in 70% of patients on angiographic scans and causes symptoms in 50% [7-10]. Angiographic vasospasm is defined as evidence of arterial narrowing compared with the parent vessels [11]. It preferentially involves the vessels of the cranial base but also may affect small-caliber vessels or diffusely the entire cerebral vascularization. The severity of vasospasm is variable. The subsequent decrease in cerebral blood flow (CBF) in the spastic arteries leads to DCI, which may develop into cerebral infarction [7,12,13].The etiology of vasospasm is complex and still poorly understood. Several factors have been shown to be involved, such as endothelial dysfunction, loss of autoregulation, and a hypovolemic component leading to a decrease in CBF [14-16]. At the acute phase, the presence of oxyhemoglobin in the subarachnoid spaces causes a local and systemic inflammatory reaction [17] with activation of platelets and coagulation [8-10]. The products derived from red blood cells (bilirubin) and endothelium (endothelin-1, free radicals) are considered to be mediators of the vasospasm [18-22] Structural anomalies in endothelial and smooth muscle cells also have been reported [23].Treatments of DCI consist of preventing or minimizing secondary injuries
Angiopoietin-1 is associated with cerebral vasospasm and delayed cerebral ischemia in subarachnoid hemorrhage
Marlene Fischer, Gregor Broessner, Anelia Dietmann, Ronny Beer, Raimund Helbok, Bettina Pfausler, Andreas Chemelli, Erich Schmutzhard, Peter Lackner
BMC Neurology , 2011, DOI: 10.1186/1471-2377-11-59
Abstract: 20 patients with subarachnoid hemorrhage (SAH) and 20 healthy controls (HC) were included in this prospective study. Blood samples were collected from days 1 to 7 and every other day thereafter. Ang-1 and Ang-2 were measured in serum samples using commercially available enzyme-linked immunosorbent assay. Transcranial Doppler sonography was performed to monitor the occurrence of cerebral vasospasm.SAH patients showed a significant drop of Ang-1 levels on day 2 and 3 post SAH compared to baseline and HC. Patients, who developed Doppler sonographic CVS, showed significantly lower levels of Ang-1 with a sustained decrease in contrast to patients without Doppler sonographic CVS, whose Ang-1 levels recovered in the later course of the disease. In patients developing cerebral ischemia attributable to vasospasm significantly lower Ang-1 levels have already been observed on the day of admission. Differences of Ang-2 between SAH patients and HC or patients with and without Doppler sonographic CVS were not statistically significant.Ang-1, but not Ang-2, is significantly altered in patients suffering from SAH and especially in those experiencing CVS and cerebral ischemia. The loss of vascular integrity, regulated by Ang-1, might be in part responsible for the development of cerebral vasospasm and subsequent cerebral ischemia.Subarachnoid hemorrhage (SAH) accounts for 2-5% of all new strokes and is still associated with high morbidity and mortality [1,2]. In about 85% of all patients, non-traumatic SAH is caused by the rupture of an intracranial aneurysm [3]. Cerebral vasospasm (CVS) is one of the most important complications of SAH and may be associated with delayed cerebral ischemia (DCI) frequently resulting in poor functional outcome and death [4-6]. Various mechanisms are discussed to be involved in the pathophysiology of CVS. Apart from smooth muscle contraction and an increase of spasmogens such as oxyhemoglobin or bilirubin oxidation products an imbalance of endothelium-
Pathophysiological Role of Global Cerebral Ischemia following Subarachnoid Hemorrhage: The Current Experimental Evidence  [PDF]
Nikolaus Plesnila
Stroke Research and Treatment , 2013, DOI: 10.1155/2013/651958
Abstract: Subarachnoid hemorrhage (SAH) is the subtype of stroke with one of the highest mortality rates and the least well-understood pathophysiologies. One of the very early events which may occur after SAH is a significant decrease of cerebral perfusion pressure (CPP) caused by the excessive increase of intracranial pressure during the initial bleeding. A severely decreased CPP results in global cerebral ischemia, an event also occurring after cardiac arrest. The aim of the current paper is to review the pathophysiological events occurring in experimental models of SAH and global cerebral ischemia and to evaluate the contribution and the importance of global cerebral ischemia for the pathophysiology of SAH. 1. Introduction Subarachnoid hemorrhage (SAH) is a relatively rare subtype of stroke (incidence: 10/100,000 person years; 5% of all first-ever strokes) which is characterized by the presence of blood in the subarachnoid space, the cerebrospinal fluid-filled space between the pia arachnoidea, a thin membrane which covers the brain parenchyma, and the dura mater [1–4]. The vast majority of SAHs (85%) is caused by the spontaneous rupture of a cerebral aneurysm located at the skull base. The consequence of blood being released into the subarachnoid space with a pressure almost equal to systolic blood pressure is that 20%–25% of patients die almost immediately after SAH [1]. From those patients reaching a hospital, 33% die within the first 30 days after hemorrhage and about 33% survive only with persisting neurological deficits making them dependent on daily care [2, 5]. The remaining 33% of patients were independent 18 months after SAH; however, only 1/3 of these patients reported no reduction in quality of life as compared to the premorbid state [6]. Accordingly, about 50% of SAHs are lethal and less than 8% of patients fully recover. Therefore, SAH is regarded as the subtype of stroke with the worst prognosis; due to the relatively young age at which SAH occurs, the loss of potential life before the age of 65 is comparable to that of ischemic stroke, a condition which is more than 20 times more frequent (incidence: 240/100,000 person years) [7]. Despite large technical and procedural achievements in the diagnosis of SAH, in the prevention of rebleedings, and in general intensive care over the past three decades, it is a matter of debate whether the outcome after SAH improved significantly [3, 5, 8, 9]. This disappointing situation may be the mere reflection of the severity of the disease, however, since most sequelae of SAH occur with a delay of several hours
Early Brain Injury: A Common Mechanism in Subarachnoid Hemorrhage and Global Cerebral Ischemia  [PDF]
Mohammed Sabri,Elliot Lass,R. Loch Macdonald
Stroke Research and Treatment , 2013, DOI: 10.1155/2013/394036
Abstract: Early brain injury (EBI) has become an area of extreme interest in the recent years and seems to be a common denominator in the pathophysiology of global transient ischemia and subarachnoid hemorrhage (SAH). In this paper, we highlight the importance of cerebral hypoperfusion and other mechanisms that occur in tandem in both pathologies and underline their possible roles in triggering brain injury after hemorrhagic or ischemic strokes. 1. Introduction Aneurysmal subarachnoid hemorrhage (SAH) is associated with significant morbidity and mortality, accounting for up to ~5% of all stroke cases [1, 2]. The mortality from SAH is estimated at 40–45% by 30 days after hemorrhagic onset and up to 15% mortality before hospital admission [3]. After years of research and extensive pathophysiological investigations of SAH, much is known in animal models about pathways that are activated after SAH and that may contribute to brain injury. However, few have proven to be effective therapeutic targets in humans [4, 5]. SAH has been suggested in multiple reports to be complex, multisystem, and multifaceted pathogenesis that likely has multiple ongoing processes activated contributing to its final pathogenesis and highly morbid manifestations [4–8]. There are some common effects, however, such as vasoconstriction of both large and small cerebral arteries. As a result, it is difficult to research one pathway, one protein, and one target for potential therapeutic benefits. There has been a shift in research to understand how all the manifestations connect, interact, and further contribute to this pathology. Many strides have been made to understand the common secondary complications that occur after SAH, especially focusing on complications that occur early on, often known as early brain injury (EBI) [9, 10]. Some of the complications that EBI encompasses are delayed neuronal injury/death (DND), oxidative stress and inflammatory destruction of the parenchyma, and ischemic deficits leading to cortical spreading depression (CSD). These complications have been theorized to play a major role in the pathogenesis and may contribute significantly to poor morbidity and outcome after SAH. Individual studies on several secondary complications have shed light on shared mechanisms and pathways that may be activated after or during or even before the hemorrhage, which may explain a number of these secondary manifestations. Research has also shifted from considering primary angiographic vasospasm as a major contributor to poor outcome to other secondary mechanisms that may also occur
Calcium and Potassium Channels in Experimental Subarachnoid Hemorrhage and Transient Global Ischemia  [PDF]
Marcel A. Kamp,Maxine Dibué,Toni Schneider,Hans-Jakob Steiger
Stroke Research and Treatment , 2012, DOI: 10.1155/2012/382146
Brain Injury after Transient Global Cerebral Ischemia and Subarachnoid Hemorrhage  [PDF]
Fatima A. Sehba,Ryszard M. Pluta,R. Loch Macdonald
Stroke Research and Treatment , 2013, DOI: 10.1155/2013/827154
Copeptin in aneurysmal subarachnoid hemorrhage
Rafael J Tamargo
Critical Care , 2012, DOI: 10.1186/cc10594
Abstract: The study by Zhu and colleagues [1], of Zhejiang University in China, in the previous issue of Critical Care is of particular interest because they report that in a population of 303 patients with aneurysmal subarachnoid hemorrhage (SAH), elevated serum copeptin levels correlated not only with poor outcomes and higher mortality but, more importantly, with vasospasm during the subacute period. A growing understanding of the pathophysiology of aneurysmal SAH has prompted efforts to identify serum markers that can predict outcomes in these patients. Since the most important treatable determinant of poor outcome after aneurysmal SAH is the delayed neurological deterioration observed 4 to 14 days after SAH (previously identified as 'vasospasm' [2] but now preferentially labeled 'delayed cerebral injury' or 'delayed cerebral ischemia'), several investigators have attempted to identify serum markers that can predict vasospasm in particular and poor functional outcome in general. Serum markers predictive of vasospasm, however, have proved elusive. For instance, the recognition of the important role of an inflammatory injury after aneurysmal SAH [3] led to an exploration of the predictive value of inflammatory markers. Recently, Juvela and colleagues [4], of the University of Helsinki in Finland, reported that elevated serum levels of C-reactive protein (an acute-phase inflammatory marker) are predictive of poor outcome at 3 months after aneurysmal SAH but not of delayed cerebral ischemia or infarction ('vasospasm'). Similarly, the recognition of the adverse changes initiated by the contact of blood with the extravascular matrix, which cause impaired coagulation and fibrinolysis, led to a prior exploration by the same group of the predictive value of elevated serum D-dimer levels. In 2006, Juvela and Siironen [5] reported that elevated serum D-dimer levels are predictive of poor outcome at 3 months after aneurysmal SAH but, again, not of delayed cerebral ischemia or infarcti
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