Atherosclerotic and inflammatory changes in saccular intracranial aneurysms

Objective Saccular intracranial aneurysm (IA) rupture causes subarachnoid hemorrhage, an acute intracranial bleeding with high mortality (30-40%) and morbidity. Unruptured IAs are common in the population (2-3%), but their rupture rate escapes prediction. Risk factors are smoking, female sex, and hypertension. Hypercholesterolemia, a risk factor for atherosclerosis, plays an unknown role in IAs. IA walls show histological changes that resemble those in atherosclerotic lesions. Altered hemodynamics are hypothesized to contribute to IA pathogenesis. Role of atherogenic mechanisms in IAs remains, however, unestablished. The aim of this thesis was to discover the role of atherosclerotic and flow-related changes as a potential trigger of IA rupture and to discuss potential tools for imaging those changes. Methods In total, 55 (25 unruptured and 30 ruptured) intraoperatively resected IA fundus specimens were evaluated by histological and immunohistochemical methods. 36 IAs underwent analysis for wall remodeling, neovascularization, lipids and apolipoproteins, erythrocyte remnants, and infiltrations of CD163+ and CD68+ macrophages, CD3+ T lymphocytes, and mast cells. Preoperative CT-angiography images provided the data source for hemodynamic simulations, compared with histology in 20 IAs. To correlate histology with MRI, 11 IAs underwent 4.7T MRI ex vivo. Results and Discussion Patient age, sex, hypertension or smoking did not associate with IA rupture or degenerative wall changes. Of 41 of the IAs, 9 showed an intact endothelium and linear smooth muscle cells (SMCs; type A, 22%), 17 showed SMC proliferation and disorganization (type B, 41%), 13 showed a hypocellular wall with a myointimal hyperplasia and/or organized thrombus (type C, 32%), and 2 showed an extremely thin, thrombosed wall (type D, 5%). Neovascularization occurred in 28/36 (78%) walls and associated with wall degeneration (type C). Hemosiderin adjacent to neovessels indicated microhemorrhages from neovessel leakage. Accumulation of lipids and apolipoproteins of HDL and LDL occurred in all 36 IAs, suggesting atherosclerotic processes, independent of plasma lipid levels. Lipid accumulation was associated with IA wall inflammation and degeneration, suggesting proinflammatory effect of lipids. Extracellular adipophilin was most extensive in ruptured IAs, reflecting death of lipid-laden cells. Cytotoxic effect of lipid may thus contribute to wall rupture. Degenerated and ruptured IAs showed a massive accumulation of erythrocytes (glycophorin A+), mainly in old thrombus. Erythrocytes associated with oxidized lipids and hemoglobin-phagocytozing macrophages. Hemoglobin may thus promote oxidative stress and inflammation in the IA wall. Glycophorin A and hemosiderin associated with signal-intensity changes ex vivo MRI, although their histological staining pattern remained unidentified in MRI. Flow models of IAs showed the association of wall shear stress with wall inflammation and remodeling, suggesting that hemodynamic simulations, as well, could serve as a tool in detection of rupture-prone human IA walls. Conclusion Aneurysm walls show a variety of degenerative remodeling changes similar to those in extracranial atherosclerosis, changes which may predispose to IA wall rupture. Experimental models are warranted to verify the suggested mechanisms. Nevertheless, the present study provides important clarification of IA-wall pathogenesis which may prove useful in development of preventive treatment for low-risk IAs and better diagnostic methods to reveal high-risk IAs.Tausta Aivovaltimon pullistuma eli aneurysma (AA) on yleinen sairaus, jota kantaa väestöstä 2-3%. Riskiä lisäävät tupakointi, naissukupuoli ja verenpainetauti. Puhkeamaton AA on yleensä oireeton. AA:n puhkeaminen aiheuttaa lukinkalvonalaisen aivoverenvuodon, jonka saaneista lähes puolet kuolee (30-40%), ja hengissä selvinneistä moni vammautuu. AA voidaan sulkea joko avoleikkauksessa (klipsaus) tai verisuonen sisältä käsin (koilaus ja/tai stenttaus). Vain osa AA:ista puhkeaa, joten kaikki AA:t eivät vaadi toimenpiteitä. Puhkeamisvaarassa olevaa AA:a ei kuitenkaan osata tunnistaa. Oikea-aikaisen hoidon kohdentamiseksi olisi ymmärrettävä, miksi AA puhkeaa. AA:n puhkeamista edeltää sen seinämän rappeutuminen. Seinämään sulautuu verihyytymää, kertyy rasvaa, ja siellä jyllää krooninen tulehdus. Kudosmuutokset muistuttavat valtimotaudin (ateroskleroosin) vaurioittamaa verisuonen seinämää. Kuluttavilla veren virtausolosuhteilla arvellaan olevan yhteys AA:n rappeutumiseen. Näiden muutosten roolia AA:ssa ei tunneta. Tutkimuksessa selvitettiin ateroskleroottisten muutosten sekä veren virtausolosuhteiden vaikutusta AA:n seinämän tulehdukseen, rappeutumiseen ja puhkeamiseen. Lisäksi selvitettiin muutosten kuvannettavuutta kokeellisella magneettikuvaustekniikalla. Menetelmät 55 leikkauksessa klipsattua AA:n seinämänäytettä (25 puhkeamatonta ja 30 puhjennutta) tutkittiin immunohistokemiallisin ja histologisin värjäyksin. 36 AA:sta tutkittiin uudisverisuonitusta ja erilaisia tulehdussoluja sekä rasva- ja punasolujätettä. 20 AA:n leikkausta edeltäneistä tietokonetomografiakuvista tehtiin matemaattinen mallinnus verenvirtausolosuhteista, ja 11 AA:aa kuvannettiin koeputkessa magneettikuvauslaitteella. Virtausmalleja ja magneettikuvia verrattiin AA:n kudostason muutoksiin. Tulokset ja Pohdinta AA-potilaan tunnetut riskitekijät tai kolesteroliarvot eivät liittyneet AA:n rappeutumiseen tai puhkeamiseen. Kaikkiin 36 AA:aan oli kertynyt rasvaa sekä kolesterolin kuljetukseen (HDL ja LDL) osallistuvia apolipoproteiineja, nämä muutokset liittyivät AA:n rappeutumiseen ja tulehdukseen. Puhjenneissa AA:n seinämässä oli runsaasti rasvaa syöneitä makrofageja ja sileälihassoluja sekä merkkejä näiden solujen kuolemasta. Rasvan kertyminen saattaa aiheuttaa tulehdusta ja solukuolemaa lisäten seinämän puhkeamisriskiä. Uudisverisuonia oli 28/36 (78%) AA:ssa, tiheimmin rappeutuneissa seinämissä. Osa uudisverisuonista näytti tihkuttaneen ympärilleen mikroverenvuotoja. Rappeutuneissa seinämissä ja vanhoissa verihyytymissä oli runsaasti punasolujen solukalvojätettä, jonka kertyminen liittyi hapettuneen rasvan ja hemoglobiinia syövien makrofagien kertymiseen. Punasolujen hajoamistuotteet todennäköisesti lisäävät AA:n seinämän hapetusta ja tulehdusta. Niiden kertyminen liittyi myös magneettikuvien signaalimuutoksiin. Yhteyden varmistamiseksi tarvitaan kuitenkin tarkempia kuvantamistutkimuksia. Virtausmalleissa kuluttava verenvirtaus liittyi seinämän tulehdukseen ja rappeutumiseen, joten myös virtausmallit voisivat tulevaisuudessa auttaa korkean vuotoriskin AA:ien tunnistamisessa. Johtopäätökset AA:n seinämässä on paljon ateroskleroosia muistuttavia rappeutumismuutoksia, jotka saattavat lisätä AA:n puhkeamisriskiä. Patologisten mekanismien varmentamiseksi tarvitaan tulevaisuudessa kokeellisia malleja. Tutkimuksessa tarkennettiin tämänhetkistä käsitystä AA:n tautitilasta ja sen mekanismeista. Uutta tietoa voidaan hyödyntää AA:n puhkeamista ehkäisevien lääkkeellisten hoitomuotojen kehittelyssä sekä korkeariskisten AA:ien tunnistamisessa potilailta

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

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

Pathways to a forest-based bioeconomy in 2060 within policy targets on climate change mitigation and biodiversity protection

While climate change and biodiversity loss have exposed humanity to major systemic risks, policymakers in more than 40 countries have proposed the transition from a fossil-based to a bio-based economy as a solution to curb the risks. In the boreal region, forests have a prominent role in contributing to bioeconomy development; however, forest-based bioeconomy transition pathways towards sustainability and the required actions have not yet been identified. Participatory backcasting was employed in this study to 'negotiate' such pathways among Finnish stakeholders by 2060 in three forest-based value networks: forest biorefineries, fibre-based packaging and wooden multistorey construction. There are many alternative pathways, ranging from incremental to more radical, to a forest-based bioeconomy within a framework of ambitious climate and biodiversity targets. Path dependence can support incremental development on bioeconomy transition pathways, and this should be considered when planning transition towards sustainability. Orchestration of the more radical changes requires actions from legislators, raw material producers, consumers and researchers, because the possibilities for business development vary between different companies and value networks. The envisioned actions between the pathways in and across the networks, such as forest diversification and diverse wood utilisation, can offer cobenefits in climate change mitigation and biodiversity protection.Peer reviewe

Gypsum amendment of arable fields as a water protection measure – farmers’ experience, phosphorus reduction potential and associated costs drawn from a large scale pilot

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Gypsum Amendment of Arable Fields – Introducing a Socially, Economically and Environmentally Sustainable National Measure in the EU CAP Support Scheme

This paper describes the development of a new and efficient agri-environmental measure, gypsum amendment of arable fields, and its inclusion as a voluntary measure in national agricultural support schemes. Gypsum reduces erosion and both particulate and dissolved reactive phosphorous loads to surface waters, thus having high potential in the Finnish agriculture in contributing Finland to meet phosphorous reduction targets set by the HELCOM Baltic Sea Action Plan. Gypsum amendment suits clayey soils located also in other Baltic Sea countries. A large scale gypsum pilot was organized in Southwest Finland, along the Savijoki River that flows to the Baltic Sea. Structured surveys and discussions in workshop explored how 55 farmers adopted gypsum amendment and gathered experience from spreading gypsum and its impacts on soils, yields and aquatic systems. Gypsum amendment is an investment in nutrient load reduction that entails high upfront costs to farmers and requiring, in case of large farms, a public tendering. As these may hinder large-scale adoption of an efficient measure, the paper suggests to include a completely new option to CAP framework: national environmental protection investments that facilitate ex-ante payment schemes to overcome the financial challenge to farmers

Gypsum amendment of agricultural fields to decrease phosphorus losses – Evidence on a catchment scale

Amending agricultural fields with gypsum has been proposed as a cost-effective measure to reduce P load on coastal waters. We treated 1490 ha of clayey fields with phosphogypsum (4 t ha− 1) in Southwest Finland and monitored the recipient river with online sensors and water sampling for the preceding spring and 5 years after the amendment. Gypsum immediately decreased the riverine fluxes, the effect lasting at least 5 years for particulate P (PP), total suspended solids (TSS), and dissolved organic C (DOC) and 1–2 years for dissolved reactive P (DRP). Compared with an upstream control area, the fluxes of PP, TSS, and DOC decreased by 15%, 25%, and 8.9%, respectively, as a 5-year average. Assuming the change in the fluxes occurred only due to gypsum, the amended fields showed 35%, 59%, and 64% lower losses for PP, TSS, and DOC than the unamended ones. More than half of the gypsum remained in the soil even after 5 years; thus, although the efficiency of gypsum lessened over time, its residual effect may be present. However, the difference in the erodibility between the control and treatment areas impacted the validity of the results, especially as the pre-gypsum period was short. In addition, the performance of gypsum showed spatial variation.Peer reviewe