Search

Background: Cerebral aneurysms (CAs) have a high prevalence in the general population and cause lethal subarachnoid hemorrhage. We recently demonstrated that chronic inflammation is an underlying pathogenesis of CA. However, we identified the negative involvement of angiotensin receptor signaling in the pathogenesis of CA., Objective: To elucidate the involvement of the renin-angiotensin system (RAS) by assessing the expression and activity of angiotensin-converting enzyme (ACE), a key enzyme of RAS, during CA formation and evaluating the effect of imidapril, an ACE inhibitor and a potent inhibitor of matrix metalloproteinase-9 (MMP-9), on CA formation., Methods: Surgically induced CA models of rats were used. Imidapril was given intraperitoneally to rats, and aneurysm size and medial thickness of CAs were examined 1 month after induction. Then, ACE and MMP-9 expression was assessed by immunostaining and Western blot analysis. The MMP-9 activity was evaluated by gelatin zymography, and ACE expression in human CA walls was assessed by immunostaining., Results: Imidapril significantly suppressed the size and medial thinning of induced CAs. The expression and activity of ACE were not induced in CA walls. Furthermore, imidapril treatment did not influence ACE expression and activity, suggesting that the inhibitory effect of imidapril was independent of an inhibition of the RAS. Imidapril inhibited MMP-9 activity upregulated in CA walls. In an in vitro study, imidapril suppressed MMP-9 activity in a dose-dependent manner. In human CA walls, as in the rat model, ACE expression was not upregulated., Conclusion: Angiotensin-converting enzyme is not involved in the pathogenesis of CA formation. Imidapril suppresses CA formation in an ACE-independent and MMP-9-dependent manner.

Objective: Recent investigations strongly suggest that the pathophysiology of cerebral aneurysms (CA) is closely associated with chronic inflammation in vascular walls. Nuclear factor kappaB (NF-kappaB) has a key role in the formation and progression of CAs. Because statins exert anti-inflammatory effects in various vascular diseases, we investigated the effect of pitavastatin on NF-kappaB activation and CA formation in experimentally induced CAs in rats., Methods: CAs were induced in Sprague-Dawley rats with or without administration of pitavastatin (4 mg/kg/d orally). Size, change of internal elastic lamina, and media thickness of induced CAs were measured in both groups after aneurysm induction. The effects of pitavastatin on NF-kappaB activation in aneurysmal walls were examined by immunohistochemistry and gel shift assay. Expression of downstream genes was analyzed by quantitative polymerase chain reaction and immunohistochemistry. To examine whether pitavastatin has a suppressive effect on preexisting CAs, pitavastatin administration started 1 month after aneurysm induction., Results: Pitavastatin treatment significantly prevented CA progression (P < 0.01) and NF-kappaB activation in aneurysmal walls. Expression of monocyte chemotactic protein-1, vascular cell adhesion molecule-1, interleukin-1beta, inducible nitric oxide synthase, and matrix metalloproteinase-9 in aneurysmal walls was also inhibited by pitavastatin. Pitavastatin treatment led to media thickening in preexisting CAs., Conclusion: Pitavastatin has a suppressive effect on CA progression through the inhibition of NF-kappaB activation in aneurysmal walls. Moreover, pitavastatin treatment can cause the regression of degenerative changes in preexisting CA walls. Pitavastatin is a promising candidate for a novel preventive agent against subarachnoid hemorrhage.

Objective: Pulsatile tinnitus is a relatively common, potentially incapacitating condition that is often vascular in origin. We present a case of disabling pulsatile tinnitus caused by a transverse-sigmoid sinus aneurysm that was surgically treated with self-tying U-clips (Medtronic, Inc., Memphis, TN). We also review the literature and discuss other described interventions., Clinical Presentation: A 48-year-old woman presented with a 5-year history of progressive pulsatile tinnitus involving the right ear. Her physical examination was consistent with a lesion that was venous in origin. Angiography demonstrated a wide-necked venous aneurysm of the transverse-sigmoid sinus that had eroded the mastoid bone., Intervention: The patient underwent a retromastoid suboccipital craniectomy to expose the aneurysm and surrounding anatomy. The aneurysm dome was tamponaded and the aneurysm neck was coagulated until the dome had shrunk to a small remnant. The linear defect in the transverse sigmoid junction was then reconstructed with a series of U-clips and covered with Gelfoam hemostatic sponge (Pfizer, Inc., New York, NY). The patient awakened without neurological deficit and with immediate resolution of her tinnitus. A postoperative angiogram demonstrated obliteration of the aneurysm, with minimal stenosis in the region of the repair and good flow through the dominant right transverse-sigmoid junction., Conclusion: This technical case report describes a novel definitive surgical treatment of venous sinus aneurysms. This technique does not necessitate long-term anticoagulation, has a low likelihood of reintervention, and provides immediate resolution of pulsatile tinnitus.

Objective: Remodeling of the saccular cerebral artery aneurysm (SCAA) wall, known to be associated with rupture, might be modified with bioactive endovascular implants or systemic drug therapy targeted at growth factor receptors to prevent rupture. The receptors regulating SCAA wall remodeling are, however, unknown., Materials and Methods: Immunostaining for 12 growth factor receptors, and markers for matrix synthesis, proliferation, and inflammatory cell infiltration, were analyzed in 21 unruptured and 35 ruptured aneurysm fundi resected after microsurgical clipping of the aneurysm neck. The results were compared with clinical and radiological data., Results: Eleven of the 12 receptors studied were expressed at varying intensities in the 56 SCAA walls. Only transforming growth factor (TGF)beta-R2 and vascular endothelial growth factor (VEGF)-R1 were associated with rupture and basic fibroblast growth factor-R1 with minor leaks (P = 0.018). TGFbeta-R3 and VEGF-R1 was associated with wall remodeling (P = 0.043 and 0.027), and VEGF-R1 was associated with T-cell and macrophage infiltration as well as organization of luminal thrombosis (P = 0.019). VEGF-R2 was associated with myointimal hyperplasia (P = 0.017) and proliferation (P < 0.001)., Conclusion: VEGF, TGFbeta, and basic fibroblast growth factor receptors were associated with SCAA wall remodeling, making them potential targets for bioactive endovascular implants or drug therapy aiming to reinforce the SCAA wall.

The etiology and pathogenesis of intracranial aneurysms are clearly multifactorial, with genetic factors playing an increasingly recognized role. Intracranial aneurysms have been associated with numerous heritable connective tissue disorders, which account for at least 5% of cases. Of these disorders, the most important are Ehlers-Danlos syndrome Type IV, Marfan's syndrome, neurofibromatosis Type 1, and autosomal dominant polycystic kidney disease; the association with intracranial aneurysms, however, has been firmly established only for polycystic kidney disease. Familial intracranial aneurysms are not rare but account for 7 to 20% of patients with aneurysmal subarachnoid hemorrhage and are generally not associated with any of the known heritable connective tissue disorders. First-degree relatives of patients with aneurysmal subarachnoid hemorrhage are at an approximately fourfold increased risk of suffering ruptured intracranial aneurysms, compared to the general population. Various possible modes of inheritance have been identified in families with intracranial aneurysms, suggesting genetic heterogeneity. Although the benefits have never been quantified, screening for asymptomatic intracranial aneurysms should be considered in families with two or more affected members. The yield of such a screening program may approximate 10%. Although it is unlikely that there is a single gene with major effect, much effort is currently being directed at locating intracranial aneurysm genes.

A European, multicenter, prospective, randomized, double-blind, dose-comparison study on preventive therapy with intravenously administered nimodipine was performed to evaluate the efficacy and tolerability of two different doses: 2 and 3 mg/h. Two hundred four patients fulfilled the criteria for enrollment in the study: surgery within 72 hours after the last subarachnoid hemorrhage, and age between 16 and 72 years. All patients who had Hunt and Hess grades of I to III were operated upon; patients who had poor Hunt and Hess grades (IV-V) were operated on according to the surgeon's choice. This treatment regimen was associated with a low incidence of delayed neurological dysfunction with no significant difference between the two dosage groups: three patients (1.5%) remained severely disabled and two (1%) moderately disabled due to vasospasm with or without additional complications. Among the patients with Hunt and Hess grades of IV or V, the long-term outcome was favorable (good-fair) for 40% and unfavorable for 60%. Among the patients with grades of I to III, the long-term outcome was favorable for 89% and unfavorable for 11%.