Aivovaltimoaneurysman inflammaatio (tulehdus) ja komplementtiaktivaatio

Intracranial artery aneurysms (IAs) are estimated to be present in 2.3% of the population. A rupture of an IA causes subarachnoid hemorrhage, with up to 50% mortality. The annual low rupture risk of an IA indicates that most IAs never rupture. The current treatment options are invasive and somewhat risky. Thus rupture-prone IAs should be identified and this requires a better understanding of the IA wall pathobiology. Inflammatory cell infiltrations have been found to precede IA rupture, indicating the role of inflammation in IA wall degeneration and rupture. The complement system is a key mediator of inflammation and house-hold processing of injured tissue. This study aimed at identifying the role of complement activation in IA wall degeneration and the complement activators involved and determining how the complement system is regulated in the IA wall. In immunostainings, the end-product of complement activation, the terminal complement complex (TCC), was located mainly in the outer part of the IA wall, in areas that had also sustained loss of cells. In electron microscopy, the area of maximum TCC accumulation contained cellular debris and evidence of both apoptotic and necrotic cell death. Complement activation correlated with IA wall degeneration and rupture, de-endothelialization, and T-cell and CD163-positive macrophage infiltration. The complement system was found to become activated in all IAs by the classical pathway, with recruitment of alternative pathway amplification. Of the potential activators immunoglobulins G and M and oxidatively modified lipids were found in large areas. Lipid accumulation was observed to clearly colocalize with TCC and C-reactive protein. In the luminal parts of the IA wall, complement activation was limited by cellular expression of protectin (CD59) and extracellular matrix-bound inhibitors, C4b binding protein and factor H whereas the outer part of the wall lacked cells expressing protectin as well as matrix-bound factor H. In single nucleotide polymorphism-analysis, age-related macular degeneration-associated factor H Y402H polymorphism did not associate with the presence of IAs or their rupture The data suggest that complement activation and TCC formation are involved in IA wall degeneration and rupture. Complement seems to become activated by more than one specific activator. The association of complement with de-endothelialization and expression of several complement activators indicate a possible role of endothelial dysfunction and/or impaired clearance mechanisms. Impaired complement regulation seems to be associated with increased complement activation in IA walls. These results stress the role of chronic inflammation in IA wall pathobiology and the regulatory role of complement within this process. Imaging inflammation would possibly enhance the diagnostics of rupture-prone IAs, and targeting IA treatment to prevent chronic inflammation might improve IA treatment in the future.Aivovaltimoaneurysma (AA) on aivoverisuonen pullistuma, jonka kantajia arvioidaan olevan Suomessa 100 000. Vuosittain noin 1000 keskimäärin työikäistä henkilöä saa AA:n puhkeamisen aiheuttaman aivoverenvuodon, johon puolet potilaista kuolee ja kolmasosalle jää pysyvä haitta. AA:n puhkeamista ei osata ennustaa eikä siihen johtavia biologisia mekanismeja tunneta tarkasti, vaikkakin tulehdussolujen kertymisen sekä AA-seinämän haurastumisen tiedetään liittyvän puhkeamiseen. Vaikka todennäköisesti osa AA:sta jääkin puhkeamatta, hoitoa ei osata toistaiseksi kohdistaa puhkeamisriskissä oleviin AA:iin eikä AA:n puhkeamista osata estää ilman leikkausta. Tässä väitöskirjatyössä tutkittiin tulehdusta välittävän komplementtijärjestelmän aktivoitumista ja säätelyä AA-kudosnäytteistä ja sekä etsittiin AA:n puhkeamista selittäviä eroja. Komplementtijärjestelmä on ryhmä veressä ja kudoksissa olevia proteiineja, joista osa osallistuu komplementin kaskadimaiseen aktivoitumiseen ja osa estää sitä. Komplementin aktivoituminen välittää inflammaatiota (steriili tulehdus ilman mikrobeja), vaurioittaa terveitä soluja ja houkuttelee tulehdussoluja, joita AA:ssa on aiemmissa tutkimuksissa havaittu. Tulehdus puolestaan voi haurastuttaa AA:n seinämää. Tulosten perusteella komplementtijärjestelmä aktivoituu kaikissa AA:ssa ja aktivaatio tapahtuu ns. klassista tietä eli tiettyjen aktivaattoreiden aiheuttamana. AA:sta löydettiin kertymiä C-reaktiivista (tulehdus)proteiinia, vasta-aineita, hapettuneita LDL-kolesterolipartikkeleita sekä kuolleita soluja, jotka kaikki voivat aktivoida komplementtia. Komplementin täydellinen aktivaatio sijoittui vyöhykemäiselle vähäsoluiselle alueelle AA:n ulkoseinämässä. Alueen laajuus liittyi selkeästi seinämän sisäsolukerroksen (endoteeli) katoamiseen, seinämän haurastumiseen, AA:n puhkeamiseen ja tiettyjen tulehdussolujen kertymiseen. Elektronimikrokopiassa komplementtiaktivaation lopputuotteita löytyi kuolleiksi soluiksi sopivista rakenteista. AA:n sisäseinämässä komplementtiaktivaatiota näytti rajoittavan soluihin ja seinämän tukiaineeseen sitoutuneet inhibiittorit (protektiini sekä C4bp ja faktori H). Näistä protektiinia ei havaittu juurikaan AA:n ulkoseinämässä. Lisäksi tutkittiin faktori H:n geneettistä Y402H-polymorfiaa, jolle ei löydetty yhteyttä AA:iin tai AA:n puhkemiseen. Tulokset osoittavat komplementtiaktivaation edeltävän AA:n puhkeamista ja liittyvän AA-seinämän haurastumiseen ja puhkeamiseen. AA-seinämän komplementtiaktivaatio näyttäisi olevan mahdollisesti seurausta usean aktivaattorin kertymisestä AA-seinämään ja liittyvän vaillinaisen aktivoitumisen eston kautta seinämäsolujen kuolemiseen. Komplementtiaktivaation tarkempi analyysi viittaa AA:n pitkäkestoiseen inflammaatioon, mikä voi olla seurausta normaalien suoja- ja puhdistusmekanismien häiriintymisestä. Saadut tulokset tuovat merkittävää lisätietoa AA-seinämän heikkenemisen mekanismeista ja saattavat ohjata puhkeamisherkkien AA:n tunnistamista ja hoitoa tulevaisuudessa

COVID-19 and SIC (!)

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Etiology and treatment patterns of ruptured extracranial carotid artery aneurysm

Objective: Rupture of an extracranial carotid artery aneurysm (ECAA) is a very rare and life-threatening condition. To obtain a comprehensive view of previous and current management of ruptured ECAAs (rECAAs), we analyzed all cases reported since 1940 and two of our own cases. Methods: We performed a comprehensive literature review of reports from the MEDLINE database on rECAAs and included two patients treated in our department. Results: A total 58 reports of 74 rECAAs in 74 patients were analyzed. Their mean age was 50 years, and the male/female ratio was 2.2:1. Infection was the most common reported etiology (19 of 74; 26%), followed by connective tissue disorder (13 of 74; 18%), atherosclerosis (9 of 74; 12%), and previous trauma (5 of 74; 7%). For 28 patients (38%), information on the etiology was not available. Of the 74 patients, 24 (32%) had undergone reconstructive surgery, 10 (14%) had undergone endovascular treatment, 17 (23%) had undergone ligation, 2 (3%) had been treated conservatively, and 1 (1%) had died before receiving definite treatment. For 20 patients (27%), information on the treatment received was not available. The complications after reconstruction included carotid blowout (3 of 24 patients; 13%) and cranial nerve deficit (3 of 24 patients; 13%). Two patients (8%) had died of unrelated ECAA causes during long-term follow-up, and one patient (4%) had died of an ECAA-related cause within 30 days. After an endovascular approach, 1 of the 10 patients had developed a cranial nerve deficit. After ligation, five patients (29%) had experienced stroke, three of which were fatal. One conservatively treated patient had experienced no complications and one had died of an ECAA-related cause. Conclusions: The most common reported etiology for rECAA was infection. Reconstructive surgery was the most common approach and was safer than ligation, which carried a high risk of stroke. Endovascular treatment showed promising results, especially for distally located aneurysms; however, the number of patients has remained low.Peer reviewe

Antitrombotisk medicinering inom kirurgin

English summary

Corrigendum to 'Editor's Choice - European Society for Vascular Surgery (ESVS) 2020 Clinical Practice Guidelines on the Management of Vascular Graft and Endograft Infections'

Non peer reviewe

Editorial : Pathophysiology and treatment of fusiform intracranial aneurysms

Non peer reviewe

Tulehdusreaktio ja aortta-aneurysman kehittyminen

English summaryPeer reviewe

Novel Locally Acting Dual Antiplatelet and Anticoagulant (APAC) Targets Multiple Sites of Vascular Injury in an Experimental Porcine Model

Objectives: Vascular binding of dual antiplatelet and anticoagulant (APAC) was assessed in surgically created femoral arteriovenous fistula (AVF) and iliac and carotid artery injury in porcine models. Methods: Three models of collagen exposing injury were used: 1) femoral AVF, 2) in vivo iliac and carotid artery balloon angioplasty injury, and 3) in vitro femoral artery endothelial denudation injury. Biotinylated APAC (0.5 mg/mL) was incubated with the injury site before releasing blood flow. APAC, von Willebrand factor (vWF), laminin, platelet endothelial cell adhesion molecule 1 (PECAM-1), and podocalyxin were detected in histological sections using immunofluorescence and confocal microscopy and Manders' co-localisation coefficient (M1). Results: APAC bound to AVF at anastomosis and to both in vivo and in vitro injured arteries. APAC co-localised with matrix vWF (M1 >= 0.66) and laminin (M1 >= 0.60), but less so if endothelial PECAM-1 or podocalyxin was present (M1 Conclusions: APAC, compatible with its high negative charge, rapidly targets injured vessels co-localizing with matrix vWF and laminin, but not with endothelial PECAM-1 and podocalyxin. This localising feature may have potential antithrombotic implications for vascular interventions.Peer reviewe

Lymphatic vessels are present in human saccular intracranial aneurysms

Saccular intracranial aneurysm (sIA) rupture leads to subarachnoid haemorrhage and is preceded by chronic inflammation and atherosclerotic changes of the sIA wall. Increased lymphangiogenesis has been detected in atherosclerotic extracranial arteries and in abdominal aortic aneurysms, but the presence of lymphatic vessels in sIAs has remained unexplored. Here we studied the presence of lymphatic vessels in 36 intraoperatively resected sIAs (16 unruptured and 20 ruptured), using immunohistochemical and immunofluorescence stainings for lymphatic endothelial cell (LEC) markers. Of these LEC-markers, both extracellular and intracellular LYVE-1-, podoplanin-, VEGFR-3-, and Prox1-positive stainings were detected in 83%, 94%, 100%, and 72% of the 36 sIA walls, respectively. Lymphatic vessels were identified as ring-shaped structures positive for one or more of the LEC markers. Of the sIAs, 78% contained lymphatic vessels positive for at least one LEC marker. The presence of LECs and lymphatic vessels were associated with the number of CD68+ and CD163+ cells in the sIA walls, and with the expression of inflammation indicators such as serum amyloid A, myeloperoxidase, and cyclo-oxygenase 2, with the presence of a thrombus, and with the sIA wall rupture. Large areas of VEGFR-3 and alpha-smooth muscle actin (alpha SMA) double-positive cells were detected in medial parts of the sIA walls. Also, a few podoplanin and alpha SMA double-positive cells were discovered. In addition, LYVE-1 and CD68 double-positive cells were detected in the sIA walls and in the thrombus revealing that certain CD68+ macrophages are capable of expressing LEC markers. This study demonstrates for the first time the presence of lymphatic vessels in human sIA walls. Further studies are needed to understand the role of lymphatic vessels in the pathogenesis of sIA.Peer reviewe

Editor's Choice - European Society for Vascular Surgery (ESVS) 2020 Clinical Practice Guidelines on the Management of Acute Limb Ischaemia

Peer reviewe