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The Pathobiology of the Saccular Cerebral Artery Aneurysm Rupture

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The Pathobiology of the Saccular Cerebral Artery Aneurysm Rupture To those of us carrying saccular cerebral artery aneurysms, - and to my family Th e Neurosurgery Research Group, Biomedicum Helsinki Department of Neurosurgery, University of Helsinki Department of Neurosurgery, University of Kuopio Transplantation Laboratory, University of Helsinki The Pathobiology of Saccular Cerebral Artery Aneurysm Rupture and Repair -a Clinicopathological and Experimental Approach Juhana Frösen ACADEMIC DISSERTATION To be publicly discussed by the permission of the Medical Faculty of the University of Helsinki in the lecture hall of Töölö Hospital on the 15th of September 2006 at 12 o’clock noon. Helsinki 2006 Supervised by Professor Juha Jääskeläinen Department of Neurosurgery Kuopio University Hospital and Marjukka Myllärniemi, MD PhD University of Helsinki Reviewed by Docent Timo Kumpulainen Department of Neurosurgery Oulu University Central Hospital and Docent Anne Räisänen-Sokolowski Department of Pathology University of Helsinki Discussed with Associate Professor Robert M Friedlander Department of Neurosurgery Harvard Medical School ISBN 952-92-0787-5 (paperback) ISBN 952-10-3330-4 (PDF) Abbreviations 15-LOX 15-lipoxygenase enzyme AAA Abdominal aortic aneurysm ACA Anterior cerebral artery AcomA Anterior communicating artery AICA Anterior inferior cerebellar artery APKD Autosomal polycystic kidney disease ApoB Apolipoprotein B ApoE Apolipoprotein E BA Basilar artery bFGF-R Receptor for basic fi broblast growth factor EEL External elastic lamina ELISA Enzyme immunoabsorbent assay eNOS Endothelial nitric oxide synthetase GDCs Guglielmi detachable coils HLA Human leukocytes antigen system ICA Internal carotid artery IEL Internal elastic lamina IGF-R Receptor for insulin-like growth factor ISAT International Subarachnoid Aneurysm Trial ISUIA International Study of Unruptured Intracranial Aneurysms LDL Low density lipoprotein MCA Middle cerebral artery MHC I Major histocompatibility complex I MHC II Major histocompatibility complex II MHOT Myointimal hyperplasia / organizing thrombosis MMPs Matrix metalloproteinases NF-kB Nuclear factor -kappa beta (a transcription factor activated by infl ammation) oxLDL Oxidatively modifi ed low density lipoprotein PCA Posterior cerebral artery PcomA Posterior communicating artery PCR Polymerase chain reaction PDGF-Rα / β Receptor for platelet derived growth factor alpha / beta PICA Posterior inferior cerebellar artery SAH Subarachnoid hemorrhage SCA Superior cerebellar artery SCAA Saccular cerebral artery aneurysm SMC Smooth muscle cell TGFβ-R Receptor for transforming growth factor beta Th 1 -cell Helper T-cell type 1 Th 2 –cell Helper T-cell type 2 VEGF-R Receptor for vascular endothelial growth factor Abbreviations 3 Original publications I. Remodeling of saccular cerebral artery aneurysm wall is associated with rupture. Histological analysis of 24 unruptured and 42 ruptured cases Juhana Frösen, MD, Anna Piippo, MB, Anders Paetau, MD PhD, Marko Kangasniemi MD PhD, Mika Niemelä, MD PhD, Juha Hernesniemi, MD PhD, Juha Jääskeläinen, MD PhD Stroke 2004;35:2287-2293. II. OxLDL accumulates in cerebral aneurysm and is targeted by plasma antibodies in SAH patients Juhana Frösen MD, Riikka Tulamo MB, Tommi Heikura MSc, Outi Närvänen MSc, Ayse Karatas MD, Mika Niemelä MD PhD, Juha Her- nesniemi MD PhD, Juha Jääskeläinen MD PhD, Anna-Liisa Levonen MD PhD, Seppo Ylä-Herttuala MD PhD. (Submitted) III. Growth factor receptor expression and remodeling of saccular cerebral artery aneurysm wall -Implications for biological therapy preventing rupture Juhana Frösen, MD, Anna Piippo, MB, Anders Paetau, MD PhD, Marko Kangasniemi MD PhD, Mika Niemelä, MD PhD, Juha Hernesniemi, MD PhD, Juha Jääskeläinen, MD PhD Neurosurgery 2006;58:534-541. IV. Contribution of mural and bone marrow-derived myointimal cells to thrombus organization and wall remodeling in a microsurgical murine saccular aneurysm model Juhana Frösen, MD, Johan Marjamaa, MD, Marjukka Myllärniemi, MD, PhD, Usama Abo-Ramadan, PhD, Riikka Tulamo, MB, Mika Niemelä, MD, PhD, Juha Hernesniemi, MD, PhD, Juha Jääskeläinen, MD, PhD Neurosurgery 2006;58:936-944. And additional unpublished data: Transfused undiff erentiated mono- nuclear cells from healthy human donors do not integrate to the bal- loon injured aorta of immunotolerant rats 4 Original publications Contents Abbreviations . .3 Original publications. .4 Abstract . .8 Introduction. 10 Review of the literature . 12 Figure 1. Saccular cerebral artery aneurysm (SCAA) . 13 Figure 2. Subarachnoid hemorrhage . 15 Figure 3. Odds ratios of SAH risk factors and the risk of SAH .....................16 Table 1. Aneurysm (A) and patient (B) related risk factors for subarachnoid hemorrhage . 16 Figure 4. Histology of extracranial and intracranial arteries . 18 Figure 5. Histology of the cerebral arteries . 19 6.1 Saccular cerebral artery aneurysms (SCAA) and subarachnoid hemorrhage (SAH) . 20 6.1.1 SAH caused by SCAA rupture . 20 6.1.2 Diagnostics of SAH and SCAAs . 22 6.1.3 Risk factors for SCAA formation and rupture . 24 6.1.4 Current therapies to prevent SCAA rupture and subsequent SAH. 27 6.1.5 Summary of current problems in the diagnostics and therapy of SCAAs . 35 6.2 Cellular and molecular pathology of the SCAA wall. 36 6.2.1 Origin of SCAAs – acquired, not congenital lesions . 36 6.2.2 Infection and infl ammation and SCAA formation . 38 6.2.3 Molecular genetics of SCAAs . 38 6.2.4 Histology of SCAA walls. 40 6.2.5 Mechanisms of SCAA wall degeneration and rupture . 42 6.2.6 Adaptation and repair mechanisms of the SCAA wall . 50 6.2.7 Summary of the putative cellular and molecular mechanisms of rupture and repair of the SCAA wall. 52 Contents 5 Aims of the study . 53 Patients, Materials and Methods . 54 8.1 Histopathological characterization of unruptured and ruptured SCAA walls (publications I, II, III) . 54 8.1.1 Tissue samples of saccular cerebral artery aneurysm fundi . 54 8.1.2 Histology and immunohistochemistry. 54 8.1.3. Detection of antibodies against OxLDL from serum samples . 56 8.1.4 Statistics . 57 Table 2. Monoclonal mouse anti-human antibodies used in Publication 1. 58 Table 3. Antibodies and dilutions used in Publication 2. 58 Table 4. Antibodies, dilutions, and controls used in Publication 3. 59 8.2 Experimental microsurgical animal models (publication IV+ additional unpublished data) . 60 Figure 6 Microsurgical experimental saccular aneurysm model in rats and mice . 61 8.2.1 Microsurgial saccular arterial aneurysm model . 62 8.2.2 Aortic balloon injury model and transplantation of human peripheral mononuclear cells (PBMCs) into immunodefi cient rats . 65 Results and Discussion. 68 Figure 7 Histology of the SCAA wall and growth factor receptor expression . 69 Figure 8 Oxidized LDL in the SCAA wall and anti-OxLDL antibodies in plasma of SCAA carriers . 71 Figure 9 Origin of neointimal cells in mouse saccular aneurysm model . 73 Figure 10 Transfused circulating human peripheral mononuclear cells in immunodefi cient rats . 75 9.1 Histopathological comparison of unruptured and ruptured SCAA walls and analysis of histological factors associated with SCAA wall rupture (publication I) . 76 9.1.1 Main fi ndings of the histological comparison of unruptured and ruptured SCAA walls . 76 9.1.2 SCAA wall degeneration and rupture-prone SCAA wall 77 9.1.3 Infl ammation and the SCAA wall . 77 9.1.4 Summary of SCAA wall remodeling and rupture risk. 78 Table 5. Patients and Histology of the SCAA wall . 79 9.2 Accumulation of OxLDL in the SCAA wall and immunization against OxLDL in SCAA carriers (publication II) . 80 6 Contents 9.2.1 Main fi ndings of immunostaining for oxidized LDL in the SCAA wall and serology for oxidized LDL in SCAA carriers and SAH patients . 80 9.2.2 Accumulation and oxidation of LDL in the saccular aneurysm wall . 80 9.2.3 Seropositivity against OxLDL antigens. 82 9.2.4 Summary of oxidized LDL, acquired humoral immunity against it, and the risk of SCAA rupture . 84 Table 6. Plasma anti-OxLDL IgG antibodies in carriers of unruptured and ruptured SCAAs. 85 9.3 Growth factor receptors, remodeling, and rupture of the SCAA wall (publication III) . 86 9.3.1 Main fi ndings of the growth factor receptor immunostainings . 86 9.3.2 Rationale for the study of growth factor receptors in the SCAA wall – Th erapeutic implications . 86 9.3.3 Limitations of immunohistochemistry . 87 Table 7. Patients and Expression of growth factor receptors in unruptured and ruptured SCAA walls . 90 9.4 Contribution of bone marrow-derived cells to thrombus organization and neointima formation in experimental aneurysms (publication IV) . 91 9.4.1 Main fi ndings of the experimental murine microsurgical saccular aneurysm models . 91 9.4.2 Signifi cance of the fi ndings . 91 9.5 Use of transfused circulating human mononuclear cells to enhance neointimal thickening –implications for the repair of the SCAA wall (unpublished data) . 93 9.5.1 Rationale of the experiments. 93 9.5.2 Main fi ndings . 93 9.5.3 Signifi cance of the fi ndings – need for in vitro manipulation or local transplantation?. 94 Conclusions . 95 Summary . 97 Future goals for basic research on the SCAA wall. 100 Yhteenveto (Summary in Finnish) . 101 Sammandrag (Summary in Swedish) . 103 Acknowledgements. 105 References . 108 Contents 7 Abstract Backround and Purpose Th e oft en fatal (in 50-35%) subarachnoid hemorrhage SAH caused by sac- cular cerebral artery aneurysm SCAA rupture aff ects mainly the working aged population. Th e incidence of SAH is 10-11 / 100 000 in Western countries and twice as high in Finland and Japan. Th e estimated preva- lence of SCAAs is around 2%. Many of those never rupture. However, cur- rently there are, however, no diagnostic methods to identify rupture-prone SCAAs from quiescent, (dormant) ones. Since SCAA rupture has such a sinister outcome, and all current treatment modalities are associated with morbidity and mortality, fi nding diagnostic markers for rupture-prone SCAAs is of primary importance since a SCAA rupture has such a sinister outcome, and all current treatment modalities are associated with morbid- ity and mortality. Also the therapies that prevent SCAA rupture need to be developed to as minimally invasive as possible.
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