Association of blood lipid levels with the risk of intracranial aneurysm formation and rupture calls for further studies : A commentary on the article by Zhang et al.

publishedVersionNon peer reviewe

Aivovaltimoaneurysman kasvua estävä lääkehoito - asetyylisalisyylihapostako ratkaisu ongelmaan?

Vuotamaton aivovaltimoaneurysma on varsin yleinen, joskin yleensä oireeton sairaus. Osa aneurysmista vuotaa, mikä aiheuttaa hengenvaarallisen kallonsisäisen verenvuodon. Kun pään kuvantamistutkimuksissa todetaan sattumalöydöksenä aneurysma, harkitaan siksi vuotoa ehkäisevää hoitoa. Vaihtoehtoina on kuitenkin toistaiseksi ollut vain merkittäviä riskejä sisältäviä kajoavia toimenpiteitä. Aivovaltimoaneurysman biologian perus- ja kliinisen tutkimuksen myötä on löytynyt mahdollisuuksia vaikuttaa vuotoriskiin lääkehoidolla. Ensimmäinen lääkehoito on Suomessakin tulossa kliinisiin kokeisiin.publishedVersionPeer reviewe

Recurrence of endovascularly and microsurgically treated intracranial aneurysmsreview of the putative role of aneurysm wall biology

Although endovascular therapy has been proven safe and has become in many centers the primary method of treatment for intracranial aneurysms, the long-term durability of endovascular embolization remains a concern; at least for some aneurysms despite initial good result. While healing after clipping relies on mechanical occlusion, restoration after endovascular occlusion mainly requires the induction of a biological response. Healing after embolization depends on the growth of new tissue over the thrombus formed by the embolization material, or alternatively, on the organization of thrombus into fibrous tissue. This review highlights the fundamental importance of aneurysm wall biology on the healing process and long-term occlusion after intracranial aneurysm (IA) treatment. It seems likely that the effect of luminal thrombus on the IA wall, as well as the IA wall condition at the time of thrombosis, determine if thrombus organizes into scar tissue (neointima formation by infiltration of cells originating from the IA wall) or if the wall undergoes continuous remodeling, which is primarily destructive (loss of mural cells). In the latter, intraluminal thrombus organization fails and the impaired healing increases the chance of recurrence. Mechanisms underlying IA reopening, the influence of intraluminal thrombosis on the IA wall, and clinical implications of the IA wall condition are discussed in detail, along with how knowledge of IA wall biology can offer new solutions for IA treatment and affect the patient selection for and follow-up after endovascular treatment.Peer reviewe

Unlike severe periodontitis, caries does not associate with intracranial aneurysms or aneurysmal subarachnoid hemorrhage.

Peer reviewe

Myeloperoxidase Associates With Degenerative Remodeling and Rupture of the Saccular Intracranial Aneurysm Wall

Rupture of a saccular intracranial aneurysm (sIA) is often fatal. Thus, early detection of rupture-prone sIAs is vital. Myeloperoxidase (MPO), derived mainly from neutrophils, associates with sIA rupture, and therefore its role in sIA pathogenesis warrants further studies. We analyzed MPO and its association with other histological markers in 36 (16 unruptured and 20 ruptured) sIA samples by immunohistochemistry. MPO was present in all studied sIAs, and its expression associated with wall inflammatory cell infiltrations (r = 0.50, 0.63, and 0.75, all p <0.002), degenerative remodeling (p = 0.002) and rupture (p = 0.003). MPO associated strongly with the presence of organized luminal thrombi (p <0.001), which also stained positive for MPO. Polymorphonuclear MPO+ cells were detected in the sIA walls, indicating neutrophils as MPO-source. MPO correlated strongly with accumulation of oxidized lipids (r = 0.67, p <0.001) and loss of smooth muscle cells (r = -0.68, p <0.001), suggesting that MPO is a relevant source of oxidative stress leading to cell death in the sIA wall. Furthermore, MPO associated with erythrocyte fragmentation (r = 0.74, p <0.001) and iron deposition (p = 0.041), 2 outcomes known to amplify MPO-dependent oxidative stress. Taken together, these results suggest that MPO associates with degenerative remodeling predisposing to sIA wall rupture and may serve as a biomarker of a rupture-prone sIA wall.Peer reviewe

The clinical course and outcomes of non-aneurysmal subarachnoid hemorrhages in a single-center retrospective study

Background: Non-aneurysmal subarachnoid hemorrhages (SAHs) are thought to have a benign clinical course compared to aneurysmal SAHs. The aim of this study is to report the clinical course and outcomes of non-aneurysmal SAHs in a large single-center study. Methods: The patients with non-aneurysmal SAHs were screened from Tampere University Hospital from 2005 to 2020. The clinical data were collected from the patient’s medical records and from the imaging studies. The primary interest was the neurological outcome assessed by dichotomized GOS at 2 months. Multivariable logistic regression was used to study the factors associated with unfavorable outcome. Results: We found 216 non-aneurysmal SAHs in 214 patients (2 patients with > 1 bleed). Ninety-seven percent of patients with a typical perimesencephalic bleeding pattern SAH (PSAH) (75/77) had a favorable outcome, while 86% of patients with non-perimesencephalic SAH (NPSAH) had a favorable outcome (84/98). In a multivariable logistic regression analysis, loss of consciousness (LOC) (aOR 214.67, 95% CI 17.62–2615.89) and Fisher grade 4 bleeding pattern (aOR 23.32, 95% CI 1.40–387.98) were associated with increased risk for unfavorable outcome (GOS 1–3). Vasospasm was seen in 20% of non-aneurysmal SAH patients, hydrocephalus in 17%, and 13% needed ventriculostomy. Conclusions: Non-aneurysmal SAH seems to have a good prognosis for majority of patients, especially for patients with a PSAH. Non-aneurysmal SAH patients are however affected by vasospasm and hydrocephalus and have similar risk factors for poor outcome as patients with aneurysmal SAH. This suggests that it is the severity of the bleed rather than the etiology that associates with poor outcome.Peer reviewe

Outcome and rational management of civilian gunshot injuries to the brain—retrospective analysis of patients treated at the Helsinki University Hospital from 2000 to 2012

Treatment of gunshot wounds of the brain (GSWB) remains controversial and there is high variation in reported survival rates (from  90%) depending on the etiology and country. We retrospectively analyzed the outcome of a series of consecutive GSWB patients admitted alive to a level 1 trauma center in a safe high-income welfare country with a low rate of homicidal gun violence.Peer reviewe

Prostaglandin E-2-EP2-NF-kappa B signaling in macrophages as a potential therapeutic target for intracranial aneurysms

Intracranial aneurysms are common but are generally untreated, and their rupture can lead to subarachnoid hemorrhage. Because of the poor prognosis associated with subarachnoid hemorrhage, preventing the progression of intracranial aneurysms is critically important. Intracranial aneurysms are caused by chronic inflammation of the arterial wall due to macrophage infiltration triggered by monocyte chemoattractant protein-1 (MCP-1), macrophage activation mediated by the transcription factor nuclear factor kappa B (NF-kappa B), and inflammatory signaling involving prostaglandin E-2 (PGE(2)) and prostaglandin E receptor subtype 2 (EP2). We correlated EP2 and cyclooxygenase-2 (COX-2) with macrophage infiltration in human intracranial aneurysm lesions. Monitoring the spatiotemporal pattern of NF-kappa B activation during intracranial aneurysm development in mice showed that NF-kappa B was first activated in macrophages in the adventitia and in endothelial cells and, subsequently, in the entire arterial wall. Mice with a macrophage-specific deletion of Ptger2 (which encodes EP2) or macrophage-specific expression of an I kappa B alpha mutant that restricts NF-kappa B activation had fewer intracranial aneurysms with reduced macrophage infiltration and NF-kappa B activation. In cultured cells, EP2 signaling cooperated with tumor necrosis factor-alpha (TNF-alpha) to activate NF-kappa B and synergistically induce the expression of proinflammatory genes, including Ptgs2 (encoding COX-2). EP2 signaling also stabilized Ccl2 (encoding MCP-1) by activating the RNA-stabilizing protein HuR. Rats administered an EP2 antagonist had reduced macrophage infiltration and intracranial aneurysm formation and progression. This signaling pathway in macrophages thus facilitates intracranial aneurysm development by amplifying inflammation in intracranial arteries. These results indicate that EP2 antagonists may therefore be a therapeutic alternative to surgery.Peer reviewe

Role of oral pathogens in the pathogenesis of intracranial aneurysm : review of existing evidence and potential mechanisms

Degeneration of intracranial aneurysm wall is under active research and recent studies indicate an increased risk of rupture of intracranial aneurysm among patients with periodontal diseases. In addition, oral bacterial DNA has been identified from wall samples of ruptured and unruptured aneurysms. These novel findings led us to evaluate if oral diseases could predispose to pathological changes seen on intracranial aneurysm walls eventually leading to subarachnoid hemorrhage. The aim of this review is to consider mechanisms on the relationship between periodontitis and aneurysm rupture, focusing on recent evidence.Peer reviewe

CNS-associated macrophages contribute to intracerebral aneurysm pathophysiology

Intracerebral aneurysms (IAs) are pathological dilatations of cerebral arteries whose rupture leads to subarachnoid hemorrhage, a significant cause of disability and death. Inflammation is recognized as a critical contributor to the formation, growth, and rupture of IAs; however, its precise actors have not yet been fully elucidated. Here, we report CNS-associated macrophages (CAMs), also known as border-associated macrophages, as one of the key players in IA pathogenesis, acting as critical mediators of inflammatory processes related to IA ruptures. Using a new mouse model of middle cerebral artery (MCA) aneurysms we show that CAMs accumulate in the IA walls. This finding was confirmed in a human MCA aneurysm obtained after surgical clipping, together with other pathological characteristics found in the experimental model including morphological changes and inflammatory cell infiltration. In addition, in vivo longitudinal molecular MRI studies revealed vascular inflammation strongly associated with the aneurysm area, i.e., high expression of VCAM-1 and P-selectin adhesion molecules, which precedes and predicts the bleeding extent in the case of IA rupture. Specific CAM depletion by intracerebroventricular injection of clodronate liposomes prior to IA induction reduced IA formation and rupture rate. Moreover, the absence of CAMs ameliorated the outcome severity of IA ruptures resulting in smaller hemorrhages, accompanied by reduced neutrophil infiltration. Our data shed light on the unexplored role of CAMs as main actors orchestrating the progression of IAs towards a rupture-prone state. Graphical abstract: (Figure presented.