Muhammad S. Ali

Biology of intracranial aneurysms: role of inflammation

Intracranial aneurysms (IAs) linger as a potentially devastating clinical problem. Despite intense investigation, our understanding of the mechanisms leading to aneurysm development, progression and rupture remain incompletely defined. An accumulating body of evidence implicates inflammation as a critical contributor to aneurysm pathogenesis. Intracranial aneurysm formation and progression appear to result from endothelial dysfunction, a mounting inflammatory response, and vascular smooth muscle cell phenotypic modulation producing a pro-inflammatory phenotype. A later final common pathway appears to involve apoptosis of cellular constituents of the vessel wall. These changes result in degradation of the integrity of the vascular wall leading to aneurysmal dilation, progression and eventual rupture in certain aneurysms. Various aspects of the inflammatory response have been investigated as contributors to IA pathogenesis including leukocytes, complement, immunoglobulins, cytokines, and other humoral mediators. Furthermore, gene expression profiling of IA compared with control arteries has prominently featured differential expression of genes involved with immune response/inflammation. Preliminary data suggest that therapies targeting the inflammatory response may have efficacy in the future treatment of IA. Further investigation, however, is necessary to elucidate the precise role of inflammation in IA pathogenesis, which can be exploited to improve the prognosis of patients harboring IA.

Cigarette Smoke and Inflammation: Role in Cerebral Aneurysm Formation and Rupture

Smoking is an established risk factor for subarachnoid hemorrhage yet the underlying mechanisms are largely unknown. Recent data has implicated a role of inflammation in the development of cerebral aneurysms. Inflammation accompanying cigarette smoke exposure may thus be a critical pathway underlying the development, progression, and rupture of cerebral aneurysms. Various constituents of the inflammatory response appear to be involved including adhesion molecules, cytokines, reactive oxygen species, leukocytes, matrix metalloproteinases, and vascular smooth muscle cells. Characterization of the molecular basis of the inflammatory response accompanying cigarette smoke exposure will provide a rational approach for future targeted therapy. In this paper, we review the current body of knowledge implicating cigarette smoke-induced inflammation in cerebral aneurysm formation/rupture and attempt to highlight important avenues for future investigation.

TNF-α induces phenotypic modulation in cerebral vascular smooth muscle cells: implications for cerebral aneurysm pathology

Little is known about vascular smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation or pathogenesis of intracranial aneurysms. Tumor necrosis factor-alpha (TNF-α) has been associated with aneurysms, but potential mechanisms are unclear. Cultured rat cerebral SMCs overexpressing myocardin induced expression of key SMC contractile genes (SM-α-actin, SM-22α, smooth muscle myosin heavy chain), while dominant-negative cells suppressed expression. Tumor necrosis factor-alpha treatment inhibited this contractile phenotype and induced pro-inflammatory/matrix-remodeling genes (monocyte chemoattractant protein-1, matrix metalloproteinase-3, matrix metalloproteinase-9, vascular cell adhesion molecule-1, interleukin-1 beta). Tumor necrosis factor-alpha increased expression of KLF4, a known regulator of SMC differentiation. Kruppel-like transcription factor 4 (KLF4) small interfering RNA abrogated TNF-α activation of inflammatory genes and suppression of contractile genes. These mechanisms were confirmed in vivo after exposure of rat carotid arteries to TNF-α and early on in a model of cerebral aneurysm formation. Treatment with the synthesized TNF-α inhibitor 3,6-dithiothalidomide reversed pathologic vessel wall alterations after induced hypertension and hemodynamic stress. Chromatin immunoprecipitation assays in vivo and in vitro demonstrated that TNF-α promotes epigenetic changes through KLF4-dependent alterations in promoter regions of myocardin, SMCs, and inflammatory genes. In conclusion, TNF-α induces phenotypic modulation of cerebral SMCs through myocardin and KLF4-regulated pathways. These results demonstrate a novel role for TNF-α in promoting a pro-inflammatory/matrix-remodeling phenotype, which has important implications for the mechanisms behind intracranial aneurysm formation.

The Role of Oxidative Stress in Cerebral Aneurysm Formation and Rupture

Oxidative stress is known to contribute to the progression of cerebrovascular disease. Additionally, oxidative stress may be increased by, but also augment inflammation, a key contributor to cerebral aneurysm development and rupture. Oxidative stress can induce important processes leading to cerebral aneurysm formation including direct endothelial injury as well as smooth muscle cell phenotypic switching to an inflammatory phenotype and ultimately apoptosis. Oxidative stress leads to recruitment and invasion of inflammatory cells through upregulation of chemotactic cytokines and adhesion molecules. Matrix metalloproteinases can be activated by free radicals leading to vessel wall remodeling and breakdown. Free radicals mediate lipid peroxidation leading to atherosclerosis and contribute to hemodynamic stress and hypertensive pathology, all integral elements of cerebral aneurysm development. Preliminary studies suggest that therapies targeted at oxidative stress may provide a future beneficial treatment for cerebral aneurysms, but further studies are indicated to define the role of free radicals in cerebral aneurysm formation and rupture. The goal of this review is to assess the role of oxidative stress in cerebral aneurysm pathogenesis.

Cigarette Smoke Modulates Vascular Smooth Muscle Phenotype: Implications for Carotid and Cerebrovascular Disease

Background The role of smooth muscle cell (SMC) phenotypic modulation in the cerebral circulation and pathogenesis of stroke has not been determined. Cigarette smoke is a major risk factor for atherosclerosis, but potential mechanisms are unclear, and its role in SMC phenotypic modulation has not been established. Methods and Results In cultured cerebral vascular SMCs, exposure to cigarette smoke extract (CSE) resulted in decreased promoter activity and mRNA expression of key SMC contractile genes (SM-α-actin, SM-22α, SM-MHC) and the transcription factor myocardin in a dose-dependent manner. CSE also induced pro-inflammatory/matrix remodeling genes (MCP-1, MMPs, TNF-α, IL-1β, NF-κB). CSE increased expression of KLF4, a known regulator of SMC differentiation, and siKLF4 inhibited CSE induced suppression of SMC contractile genes and myocardin and activation of inflammatory genes. These mechanisms were confirmed in vivo following exposure of rat carotid arteries to CSE. Chromatin immune-precipitation assays in vivo and in vitro demonstrated that CSE promotes epigenetic changes with binding of KLF4 to the promoter regions of myocardin and SMC marker genes and alterations in promoter acetylation and methylation. Conclusion CSE exposure results in phenotypic modulation of cerebral SMC through myocardin and KLF4 dependent mechanisms. These results provides a mechanism by which cigarette smoke induces a pro-inflammatory/matrix remodeling phenotype in SMC and an important pathway for cigarette smoke to contribute to atherosclerosis and stroke.

Analysis of nonmodifiable risk factors for intracranial aneurysm rupture in a large, retrospective cohort.

BACKGROUND The risk factors predictive of intracranial aneurysm rupture remain incompletely defined. OBJECTIVE To examine the association between various nonmodifiable risk factors and aneurysm rupture in a large cohort of patients evaluated at a single institution. METHODS A retrospective analysis of patients admitted to a cerebrovascular facility between January 2006 and 2010 with a primary diagnosis of cerebral aneurysm. Aneurysms were divided into 2 groups: unruptured or ruptured. The dome diameter, aspect ratio (AR), location, sidedness, neck morphology, and multiplicity were entered into a central database. A full model was constructed, and a systematic removal of the least significant variables was performed in a sequential fashion until only those variables reaching significance remained. RESULTS We identified 2347 patients harboring 5134 individual aneurysms, of which 34.90% were ruptured and 65.09% were unruptured. On admission, 25.89% of aneurysms with a dome diameter <10 mm and 58.33% of aneurysms with a dome >10 mm were ruptured (P < .001). Of aneurysms with an AR >1.6, 52.44% presented following a rupture (P < .001). The highest incidence of rupture (69.21%) was observed in aneurysms with an AR >1.6, dome diameter <10 mm, and a deviated neck. Deviated neck-type aneurysms had a significantly greater incidence of rupture than classical neck-type aneurysms (P < .001). CONCLUSION An AR >1.6, dome diameter >10 mm, a deviated neck, and right-sidedness are independently associated with aneurysm rupture.

Treatment of Small Ruptured Intracranial Aneurysms: Comparison of Surgical and Endovascular Options

Background Small intracranial aneurysms pose significant challenges to endovascular therapy. Surgical clipping is considered by many to be the preferred treatment for these lesions. We present the results of the first study comparing the 2 treatment modalities in small ruptured aneurysms. Methods and Results Between 2004 and 2011, 151 patients with small ruptured aneurysms (≤3 mm) were treated in our institution: 91 (60.3%) with endovascular therapy and 60 (39.7%) with surgical clipping. The surgical and endovascular groups were generally comparable with regard to baseline demographics, with the exception of larger mean aneurysm size in the endovascular group versus the surgical group (2.8 versus 2.5 mm, respectively; P<0.001) and a higher proportion of posterior circulation aneurysms in the endovascular group. Endovascular treatment failed in 9.9% of patients. Procedure-related complications occurred in 23.3% of surgical patients versus 9.8% of endovascular patients (P=0.01). Only 3.7% of patients undergoing endovascular therapy experienced an intraprocedural aneurysm rupture. There were no procedural deaths or rehemorrhages in either group. The rates of aneurysm recanalization and retreatment after endovascular therapy were 18.2% and 12.7%, respectively. Favorable outcomes (moderate, mild, or no disability) were not statistically different between the endovascular (67.1%) and surgical (56.7%) groups (P=0.3). Conclusions Surgical clipping was associated with a higher rate of periprocedural complications, but overall disability outcomes were similar. Endovascular therapy, if technically feasible, might be a preferred option in this setting. Inclusion of patients with small aneurysms in randomized controlled trials seems feasible and will be needed to provide definitive information on the best therapeutic approach. (J Am Heart Assoc. 2012;1:e002865 doi: 10.1161/JAHA.112.002865.)

Computed tomography perfusion-based selection of patients for endovascular recanalization.

Intravenous and intraarterial recombinant tissue plasminogen activator remains underutilized in the treatment of acute ischemic stroke, largely due to strict adherence to the concept of the therapeutic time window for administration. Recent efforts to expand the number of patients eligible for thrombolysis have been mirrored by an evolution in endovascular recanalization technology and techniques. As a result, there is a growing need to establish efficient and reliable means by which to select candidates for endovascular intervention beyond the traditional criteria of time from symptom onset. Perfusion imaging techniques, particularly CT perfusion used in combination with CT angiography, represent an increasingly recognized means by which to identify those patients who stand to benefit most from endovascular recanalization. Additionally, CT perfusion and CT angiography appear to provide sufficient data by which to exclude patients in whom there is little chance of neurological recovery or a substantial risk of postprocedure symptomatic intracranial hemorrhage. The authors review the current literature as it pertains to the limitations of time-based selection of patients for intervention, the increasing utilization of endovascular therapy, and the development of a CT perfusion-based selection of acute stroke patients for endovascular recanalization. Future endeavors must prospectively evaluate the utility and safety of CT perfusion-based selection of candidates for endovascular intervention.

Endovascular treatment of very small ruptured intracranial aneurysms: complications, occlusion rates and prediction of outcome

Objective To assess predictors of outcome following endovascular treatment of small ruptured intracranial aneurysms (SRA). Methods Between 2004 and 2011, 91 patients with SRA (≤3 mm) were treated at our institution. Multivariate analysis was carried out to assess predictors of endovascular-related complications, aneurysm obliteration (>95%), recanalization and favorable outcome (Glasgow Outcome Scale 3–5). Results Endovascular treatment was aborted in nine of 91 patients (9.9%). Procedure-related complications occurred in eight of 82 patients (9.8%) of which five were transient and three were permanent. Three patients (3.7%) undergoing endovascular treatment experienced an intraprocedural aneurysm rupture. Three of nine patients (33.3%) treated with stent- or balloon-assisted coiling experienced periprocedural complications compared with five of 73 patients (6.8%) receiving only coils or Onyx (p=0.039). There were no procedural deaths or rehemorrhages. Rates of recanalization and retreatment were 18.2% and 12.7%, respectively. No factors predicted initial occlusion or recanalization. In multivariate analysis, pretreatment factors predictive of a favorable outcome included younger age (OR 0.94; 95% CI 0.91 to 0.99, p=0.017), larger aneurysm size (OR 3.4; 95% CI 1.02 to 11.11, p=0.045), Hunt and Hess grade (OR 0.38; 95% CI 0.19 to 0.75, p=0.005) and location (OR 5.12; 95% CI 1.29 to 20.25, p=0.02). When assessing treatment and post-treatment variables, vasospasm was the only additional covariate predictive of a poor outcome (OR 5.90; 95% CI 1.34 to 25.93,p=0.019). Conclusions Most patients with SRA can be treated with endovascular therapy and have limited complications. Overall predictors of outcome for patients undergoing endovascular treatment of SRA include age, aneurysm size, Hunt and Hess grade, location and post-treatment vasospasm.

Intracranial Vertebral Artery Dissections: Evolving Perspectives

Intracranial vertebral artery dissection (VAD) represents the underlying etiology in a significant percentage of posterior circulation ischemic strokes and subarachnoid hemorrhages. These lesions are particularly challenging in their diagnosis, management, and in the prediction of long-term outcome. Advances in the understanding of underlying processes leading to dissection, as well as the evolution of modern imaging techniques are discussed. The data pertaining to medical management of intracranial VADs, with emphasis on anticoagulants and antiplatelet agents, is reviewed. Surgical intervention is discussed, including, the selection of operative candidates, open and endovascular procedures, and potential complications. The evolution of endovascular technology and techniques is highlighted.