Background and Purpose: Subarachnoid hemorrhage attributable to saccular intracranial aneurysm (IA) rupture is a devastating disease leading to stroke, permanent neurological damage and death. Despite rapid advances in the development of endovascular treatment (EVT), complete and long lasting IA occlusion remains a challenge, especially in complexly shaped and large-sized aneurysms. Intraluminal thrombus induced by EVT may recanalize. The biological mechanisms predisposing IA to recanalize and grow are not yet fully understood, and the role of mural cell loss in these processes remains unclear. To elucidate these processes, animal models featuring complex aneurysm architecture and aneurysm models with different wall conditions (such as mural cell loss) are needed.
Materials and Methods: Complex bilobular, bisaccular and broad-neck venous pouch aneurysms were microsurgically formed at artificially created bifurcations of both common carotid arteries in New Zealand rabbits. Sidewall aneurysms were microsurgically created on the abdominal aorta in Wistar rats. Some sidewall aneurysms were decellularized with sodium dodecyl sulfate. Thrombosis was induced using direct injection of a fibrin polymer into the aneurysm. CM-Dil-labeled syngeneic smooth muscle cells were injected into fibrin embolized aneurysms. The procedures were followed up with two-dimensional intra-arterial digital subtraction angiography, contrast-enhanced serial magnetic resonance angiographies, endoscopy, optical projection tomography, histology and immunohistochemistry.
Results: Aneurysm and parent vessel patency of large aneurysms with complex angioarchitecture was 90% at one month and 86% at one year follow-up in the bifurcation rabbit model. Perioperative and one month postoperative mortality and morbidity were 0% and 9%. Mean operation time in the rat model was less than one hour and aneurysm dimensions proved to be highly standardized. Significant growth, dilatation or rupture of the experimental aneurysms was not observed, with a high overall patency rate of 86% at three week follow-up. Combined surgery-related mortality and morbidity was 9%. Decellularized aneurysms demonstrated a heterogeneous pattern of thrombosis, thrombus recanalization and growth, with ruptures in the sidewall rat model. Aneurysms with intraluminal local cell replacement at the time of thrombosis developed better neointima, showed less recurrence or growth and no ruptures. Growing and ruptured aneurysms demonstrated marked adventitial fibrosis and inflammation, complete wall disruption and increased neutrophil accumulation in unorganized luminal thrombus.
Conclusions: Creation of complex venous pouch bifurcation aneurysms in the rabbit is feasible, with low morbidity, mortality and high short-term and long-term aneurysm patency. They represent a promising approach for in vivo animal testing of novel endovascular therapies. The sidewall aneurysm rat model is a quick and consistent method to create standardized aneurysms. Aneurysms missing mural cells are incapable of organizing a luminal thrombus, leading to aneurysm recanalization and increased inflammatory reactions. These, in turn, result in severe wall degeneration, aneurysm growth and eventual rupture. The results of the presented studies suggest that the biologically active luminal thrombus drives the healing process towards destructive wall remodeling and aneurysm rupture. Local smooth muscle cell transplantation compensates for mural cell loss and reduces recurrence, growth and rupture rate in a sidewall aneurysm rat model.Aivovaltimopullistuman repeämisestä johtuva lukinkalvonalinen verenvuoto (subaraknoidaalivuoto, SAV) on äkillinen ja raju kallonsisäinen verenvuoto joka tapahtuu noin tuhannelle henkilölle suomessa per vuosi. SAV aiheuttaa pysyvän neurologisen haitan tai kuoleman valtaosalle potilaista. Aivovaltimopullistumia voidaan hoitaa joko mikrokirurgisella leikkauksella tai tukkimalla pullistuma suonensisäisesti (endovaskulaarinen hoito). Suonesisäiset hoitomenetelmät ovat viime vuosikymmeninä kehittyneet merkittävästi, mutta edelleen osaa pullistumista ei voida tällä menetelmällä hoitaa ja ajoittain hoidon tulos ei ole pitkällä aikavälillä pysyvä.
Suonensisäisten hoitomenetelmien jatkokehittämiseksi tarvitaan enemmän tietoa aivovaltimopullistuman seinämässä tapahtuvista biologisista mekanismeista ja realistisempiä kokeellisia malleja, mukaan lukien koe-eläinmalleja, joissa hoitomenetelmiä voidaan testata.
Tässä väitöskirjassa on syvennytty tutkimaan kahta eri koe-eläinmallia, kani- ja rottamallia. Väitöskirjassa osoitetaan että mallit soveltuvat suonensisäisten hoitomenetelmien testaamiseen. Malleissa on kyetty realistisella tavalla mallintamaan todellisen aivovaltimopullistuman eri rappeutuneisuusasteita ja saatu merkittävää lisätietoa siitä miten pullistuman seinämän biologiset tapahtumat joko vahvistavat seinämää tai altistavat seinämän repeämiselle
