Vascular Inflammation in Rheumatic And

Vascular Inflammation in Rheumatic and Non- rheumatic Patients: A Controlled Study of Biopsy Specimens Obtained During Coronary Artery Surgery (Feiring Heart Biopsy Study) Doctoral thesis by Ivana Hollan Hospital for Rheumatic Diseases, Lillehammer, Norway The Feiring Heart Clinic, Feiring, Norway Rikshospitalet-Radiumhospitalet University Hospital, Oslo, Norway University of Oslo, Norway 2009 ISBN 978-82-8072-766-4 © Ivana Hollan, 2009 Series of dissertations submitted to the Faculty of Medicine, University of Oslo No. 779 ISBN 978-82- 8072-766-4 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Inger Sandved Anfinsen. Printed in Norway: AiT e-dit AS, Oslo, 2009. Produced in co-operation with Unipub AS. The thesis is produced by Unipub AS merely in connection with the thesis defence. Kindly direct all inquiries regarding the thesis to the copyright holder or the unit which grants the doctorate. Unipub AS is owned by The University Foundation for Student Life (SiO) 3 Imagination is more important than knowledge. For knowledge is limited to all we now know and understand, while imagination embraces the entire world, and all there ever will be to know and understand. Albert Einstein (1879-1955) 4 Content Acknowledgements 6 Abbreviations 8 List of papers 9 1. Introduction 10 1.1 Cardiovascular complications in inflammatory rheumatic diseases 10 1.1.1 Coronary artery disease in inflammatory rheumatic diseases 10 1.1.2 Cardiac involvement in spondyloarthritides 11 1.2 Causes of vascular lumen narrowing 11 1.2.1 Aortic and cardiac vasculitis 12 1.2.2 Diagnostic challenges in detecting aortic and cardiac vasculitis 13 1.3 Link between atherosclerosis and inflammation 14 1.4 Resistance to atherosclerosis in different vessels 16 1.5 The driving force behind the study 16 2. Main hypotheses and aims 18 3. Methods 19 3.1 Patients 19 3.1.1 Patient groups described in Papers I and II 19 3.1.2 Patient groups described in Paper III 20 3.1.2 Other patient groups (biobank) 20 3.2 Data collection 20 3.2.1 CAD-IRD and CAD-nonIRD groups 20 3.2.2 Healthy controls and RA patients without cardiovascular 23 complications 3.2.3 Non-SpA group 23 3.3 Ethics 24 3.4 Statistics 24 4. Summary of results 25 4.1 Paper I 25 4.2 Paper II 26 4.3 Paper III 29 5. General discussion 31 5.1 Methodological aspects 31 5.1.1 Study design 31 5.1.2 Patients 31 5.1.3 Data collecting and processing 32 5.2 Main results 33 5.2.1 Inflammation and atherosclerosis in the aorta, saphenous vein, and 33 IMA 5.2.2 Premature coronary artery bypass surgery in spondyloarthritides 36 5.3 Prospective for future studies 37 6. Conclusions and clinical implications 38 Reference list 39 Appendix: Papers I-III 50 5 Acknowledgements I thank all of you who have made my doctoral fellowship an enjoyable and exciting event. First of all, I would like to thank my main tutor, professor emeritus Øystein T. Førre, MD, PhD (University of Oslo, Norway), for his help. Although conflicts between PhD students and their mentors are common, our relationship grew even stronger during our co- operation. I really appreciate that his loyalty and friendship continue even when our opinions differ. That also applies to the Head of the Hospital for Rheumatic Disease in Lillehammer, Knut Mikkelsen, MD. Knut made it possible for me to engage in research and to establish collaboration with our outstanding collaborators. He helped me to believe in myself and in the possibilities to reach my goals. His enthusiasm and positive attitude are outstanding. I am grateful to professor Hans Nossent, MD, PhD (Department of Rheumatology, University Hospital of North Norway, Tromsø), for his help in choosing the topic, and for his support and thorough guidance. This study would not have been possible without Kjell Saatvedt, MD, PhD (Department of Thoracic Surgery, Rikshospitalet-Radiumhospitalet University Hospital, Oslo). He saw the possibility in removing aortic tissue during coronary artery bypass grafting. His ability to act was amazing; he helped me to establish the project at the Feiring Heart Clinic. Also, his encouraging words filled me with the energy necessary to carry out the project. I am indebted to professor Truls Myrmel, MD, PhD (Department of Cardiothoracic Surgery, University Hospital of North Norway, Tromsø) and Sigurd Birkeland, MD (Department of Thoracic Surgery, the Feiring Heart Clinic, Norway), for their support and important advice regarding the taking of vascular biopsy collection. I would like to express my sincere gratitude to professor Helge Scott, MD, PhD (Department of Pathology, Rikshospitalet-Radiumhospitalet University Hospital, Oslo), professor Richard Prayson, MD (Department of Anatomic Pathology, Cleveland Clinic Foundation, Cleveland, USA), Ingjerd Lien Kvelstad, MD, and Eldbjørg Sandstad, MD (Department of Pathology, Innlandet Hospital Trust, Lillehammer) for their invaluable help, guidance, practical assistance and thorough evaluation of the biopsies. I am indebted to the department of pathology at Innlandet Hospital Trust, Lillehammer for giving me the opportunity to take pictures of the histological sections. I am grateful to professor Matthew Liang MD, MPH (Department of Rheumatology, Brigham and Women’s Hospital, Boston, USA), for his critical but kind advice throughout the whole project period. I would like to acknowledge all other persons involved in the planning of the study and/or performing of laboratory analyses: professor Pål Aukrust, MD, PhD, Jan Kristian Damås, MD, PhD, Arne Yndestad, MSc.Pharm., PhD, Ove Johan Mellbye, MD, PhD, Johan Kofstad, Tor-Arne Hagve, MD, PhD, and professor Frank Brosstad, MD, PhD (Rikshospitalet-Radiumhospitalet University Hospital, Oslo), professor emeritus Magne Fagerhol, MD, PhD (Ullevaal University Hospital, Oslo), professor Pier Luigi Meroni, MD (Istituto Auxologico Italiano, Milan, Italy), professor Gunnar Sturfelt, MD, PhD (University Hospital, Lund, Sweden), professor Ingrid Lundberg, MD, PhD, and Cecilia Grundtman, MD, PhD (Karolinska University Hospital, Stockholm, Sweden), professor Manuela Nebuloni, MD, (Università degli Studi di Milano, Milan), professor Herbert Virgin, MD, PhD (Washington University, St. Louis, USA), professor Ian McInnes, MD, PhD (University of Glasgow, UK), professor Per Venge, MD, PhD (University Hospital, Uppsala, Sweden), and Carola Grub, MD (Innlandet Hospital Trust, Lillehammer). I will give special thanks to professor Susan Manzi, MD, MPH, and professor Joseph Ahearn, MD (University of Pittsburgh School of Medicine, Pittsburgh, USA), professor Allan Wiik, MD, DSc. (Med) (Statens Serum Institut, Copenhagen), and Torstein Lyberg, MD, PhD (Ullevaal University 6 Hospital, Oslo), for their support and enjoyable discussions. Meeting such people outweighs the disappointments associated with research. I am grateful to the administrative board of the Hospital for Rheumatic diseases and the Feiring Heart Clinic for the flexibility, novel thinking, and establishment of a common post for this doctoral fellowship. I am deeply indebted to Vemund Vigerust, who was the director of the Hospital for Rheumatic Disease in Lillehammer during the initial phase of the project. His help and attitude made all challenges to appear small and manageable, and his acknowledgements inspired to accomplish difficult tasks. I am grateful to the staff at the Feiring Heart Clinic, especially the physicians, nurses, and secretarial and technical assistants, for their help in the inclusion of the patients, collecting of the specimens and data, and technical support. Sven Roger Tufteland accomplished a great assistance in collection of the specimens. Without Inger Lise Nævdal, the study would be almost undoable: she had a central role in the screening of the surgical patients for inflammatory rheumatic diseases. I really appreciate the reliability and the positive attitude of Sven Martin Almdahl, who collected many of the specimens, and offered important advice. I thank Rasmus Moer, MD, PhD (the Feiring Heart Clinic), for guidance and practical help. I thank Terje Veel, MD, PhD, Per Halvorsen, MD, and many others, whom I am not able to list by names because of the limit space of this thesis, but to whom I am extremely thankful. I thank Birgitte Omtvedt, Marit Moen, and Bente Børresen at the Hospital for Rheumatic Diseases in Lillehammer for laboratory assistance, and Bente C. Edvardsen and Kari Hansen Berg for the secretarial and administrative assistance. I thank Geir Aamodt, PhD (Norwegian Institute of Public Health, Oslo) and for statistical advice. I thank professor Gary S. Hoffman, MD, MS (Cleveland Clinic Foundation, Cleveland), professor John Kjekshus, MD, PhD (Rikshospitalet-Radiumhospitalet University Hospital, Oslo) for their valuable advice. I am really impressed by their generosity and willingness to help. I thank the Eastern Norway Regional Health Authority, the Norwegian Association for People with Heart and Lung Diseases, the Norwegian Society for Rheumatology, the Norwegian Rheumatism Association, the Oppland county branch of the Norwegian Rheumatism Association, the Norwegian Women’s Public Health Association, Eimar Munthe’s Memorial Fund, Alf and Aagot Helgesen’s Fund and Sigval Bergesen and Hustru Nanki’s Public Utilities Foundation for financial support. I thank the Norwegian Rheumatism Association and the Norwegian Association for People with Heart and Lung Diseases for the financial support as well as for their faith in my work. I thank

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