Physics of blood flow in arteries and its relation to intra-luminal thrombus and atherosclerosis Jacopo Biasetti Doctoral thesis no. 84, 2013 KTH School of Engineering Sciences Department of Solid Mechanics - vascuMECH KTH Royal Institute of Technology SE-100 44 Stockholm, Sweden TRITA HFL-0546 ISSN 1104-6813 ISRN KTH/HFL/R-13/14-SE ISBN 978-91-7501-836-2 Akademisk avhandling som med tillst˚andav Kungliga Tekniska H¨ogskolan i Stockholm framl¨aggestill offentlig granskning f¨oravl¨aggandeav teknisk doktorsexamen torsdag den 22 augusti kl. 10.00 i sal F3, Kungliga Tekniska H¨ogskolan, Lindstedtsv¨agen26, Stockholm. Abstract Vascular pathologies such as Abdominal Aortic Aneurysm (AAA) and atherosclerosis are complex vascular diseases involving biological, mechanical, and fluid-dynamical factors. This thesis follows a multidisciplinary approach and presents an integrated fluid-chemical theory of ILT growth and analyzes the shear-induced migration of red blood cells (RBCs) in large arteries with respect to hypoxia and its possible role in atherosclerosis. The concept of Vortical Structures (VSs) is employed, with which a theory of fluid-chemically-driven ILT growth is formulated. The theory proposes that VSs play an important role in convecting and activating platelets in the aneurysmatic bulge. In particular, platelets are convected toward the distal aneurysm region inside vortex cores and are activated via a combination of high residence times and relatively high shear stress at the vortex boundary. After vortex break- up, platelets are free to adhere to the thrombogenic wall surface. VSs also convect thrombin, a potent procoagulant enzyme, captured in their core, through the aneurysmatic lumen and force its accumulation in the distal portion of the AAA. This framework is in line with the clinical observation that the thickest ILT is usually seen in the distal AAA region. The investigation of the fluid-dynamics in arteries led to the study of the shear-induced migration of RBCs in large vessels such as the abdominal aorta and the carotid artery. Marked RBCs migration is observed in the region of the carotid sinus and in the iliac arteries, regions prone to atherogenesis. This leads to the hypothesis that oxyhemoglobin availability can decrease in the near-wall region thus contributing to wall hypoxia, a factor implicated in atherosclerosis. The thesis proposes a new potential mechanism of ILT growth, driven by fluid and chemical stimuli, which can be used to study ILT progression over physiologically relevant timeframes and be used as a framework to test new hypotheses; the thesis also provides new insights on the oxyhemoglobin availability in the near-wall region with direct influence on atherosclerosis. Sammanfattning Patologier s˚asombukaortaaneurysm och ˚aderf¨orkalkning ¨arkomplexa vaskul¨arasjukdomar som involverar biologiska, mekaniska och str¨omningsmekaniska faktorer. Denna avhandling f¨oljerett multidisciplin¨arttillv¨agag˚angss¨attoch presenterar en integrerad str¨omnings-kemisk teori g¨allandeILT-tillv¨axtoch analyserar den skjuvinducerade migrationen av r¨odablod- celler (RBCs) i stora art¨arermed avseende p˚ahypoxi och dess m¨ojligaroll i ˚aderf¨orkalkning. Konceptet innefattande virvelstrukturer anv¨ands,med vilken en teori g¨allandestr¨omnings- kemiskt driven ILT-tillv¨axtformuleras. Teorin f¨oresl˚aratt virvelstrukturer har en viktig roll i att transportera och aktivera blodpl¨attari den aneurysmatiska ansv¨allningen.Blodpl¨attar transporteras till den distala aneurysmregionen inuti virvelk¨arnoroch aktiveras via en kom- bination av en l˚anguppeh˚allstid och relativt h¨ogskjuvsp¨anningvid virvelgr¨ansen. Efter att virveln har brutits upp kan blodpl¨attarnaobehindrat f¨astasig vid den trombogeniska v¨aggytan. Virvelstrukturerna transporterar ¨aven trombin, ett potent prokoagulant enzym, f˚angati k¨arnan,genom det aneurysmatiska h˚alrummetoch p˚atvingard¨armeden ansamling i den distala delen av bukaortaaneurysmen. Denna struktur ¨overensst¨ammermed den kliniska observationen att den tjockaste delen av ILT ses oftast i den distala regionen av bukaor- taaneurysmen. Unders¨okningenav str¨omningsmekaniska aspekter i art¨arerledde till studien av skjuvsp¨anningsinduceradmigration av RBCs i stora k¨arls˚asomden abdominala aortan och halspuls˚adern.Markant RBC-migration kan observeras i regionen kring halspuls˚aderns sinus och i iliacaart¨arerna,regioner som ¨arben¨agnaatt utveckla aterogenes. Detta leder till hypotesen att tillg¨anglighetenp˚aoxyhemoglobin kan minska i regionen n¨arav¨aggenoch d¨armedbidra till v¨agghypoxi, en faktor som impliceras i ˚aderf¨orkalkning. Denna avhandling framl¨aggeren ny potentiell mekanisk f¨orILT-tillv¨axt,driven av stimuli fr˚anstr¨omnings- mekaniska och kemiska faktorer, som kan anv¨andasf¨oratt unders¨oka utveckling av ILT ¨over fysiologiskt relevanta tidsskalor och kan anv¨andas som en metod f¨oratt pr¨ova nya hypoteser; avhandlingen tillf¨orocks˚anya insikter g¨allande tillg¨anglighetenav oxyhemoglobin i regionen n¨arav¨aggenmed direkt influens p˚a˚aderf¨orkalkning. Preface The present work has been financially supported by the Young Faculty Grant No. 2006- 7568 provided by the Swedish Research Council, VINNOVA and the Swedish Foundation for Strategic Research and by the Project Grant No. 2010-4446 from the Swedish Research Council, which are gratefully acknowledged. Stockholm, July 2013 To Barbara... ...Thank you List of appended papers Paper A: Hemodynamics conditions of the normal aorta compared to fusiform and saccular abdominal aortic aneurysms with emphasis on a potential thrombus formation mechanism J. Biasetti, T. C. Gasser*, M. Auer, U. Hedin and F. Labruto Ann. Biomed. Eng., 38:380-390, 2009 (doi:10.1007/s10439-009-9843-6). Paper B: Blood flow and coherent vortices in the normal and aneurysmatic aortas: a fluid dynamical approach to intra-luminal thrombus formation J. Biasetti*, F. Hussain and T. C. Gasser J. R. Soc. Interface, 8:1449-1461, 2011 (doi:10.1098/rsif.2011.0041). Paper C: An integrated fluid-chemical model toward modeling the formation of intra-luminal thrombus in abdominal aortic aneurysms J. Biasetti*, P. G. Spazzini, J. Swedenborg and T. C. Gasser Front Physiol., 3:266, 2012 (doi: 10.3389/fphys.2012.00266). Paper D: Shear-induced migration of red blood cells in the abdominal aorta and the carotid bifurcation: considerations on oxygen transport J. Biasetti*, P. G. Spazzini and T. C. Gasser To be submitted In addition to the appended papers, the work has resulted in the following publications and presentations1: Biomechanical determinants of Abdominal Aortic Aneurysms - fusiform versus pseudo(saccular) formations J. Biasetti, M. Auer, T.C. Gasser, U. Hedin and J. Swedenborg WCCM8 and ECCOMAS, Venice, Italy, June 30 - July 5, 2008 (O) Hemodynamic simulations towards a biomechanical model of thrombus formation in Abdominal Aortic Aneurysm J. Biasetti, T.C. Gasser, M. Auer, U. Hedin and F. Labruto Endovascular Surgery - Bringing Basic Science into Clinical Practice, Stockholm, Sweden, March 19-21, 2009 (O) Hemodynamic simulations in Abdominal Aortic Aneurysms - Insights into throm- bus formation J. Biasetti, T.C. Gasser, M. Auer, U. Hedin and F. Labruto 10th US National Congress on Computational Mechanics, Columbus, Ohio, US, July 16-19, 2009 (O) Structural and hemodynamical analysis of Aortic Aneurysms from Computerized Tomography Angiography data T. C. Gasser, M. Auer and J. Biasetti 1O = Oral presentation, P = Poster presentation Proceedings of the World Congress 2009 - Medical Physics and Biomedical Engineering, Mu- nich, Germany, September 7-12, 2009 (O) Coherent structure and blood flow dynamics in the normal and aneurysmatic aorta J. Biasetti, F. Hussain and T.C. Gasser ECCOMAS CFD 2010 - Fifth European Conference on Computational Fluid Dynamics, Lis- bon, Portugal, June 14-17, 2010 (O) A blood flow based model for platelet activation in Abdominal Aortic Aneurysms J. Biasetti and T.C. Gasser WCB 2010 - 6th World Congress on Biomechanics, Singapore, Singapore, August 1-6, 2010 (O) A fluido-chemical model of Thrombus formation J. Biasetti and T.C. Gasser CMBE 2011 - 2nd International Conference on Mathematical and Computational Biomedical Engineering, Washington D.C., USA, March 30 - April 1, 2011 (O) The Intra-Luminal Thrombus in Abdominal Aortic Aneurysms: a fluido-chemical approach to explain its development J. Biasetti and T.C. Gasser 6th International Symposium on Biomechanics in Vascular Biology and Cardiovascular Dis- ease, Rotterdam, The Netherland, April 14-15, 2011 (P) An integrated fluid-chemical model towards modeling the formation of Intra- Luminal Thrombus in Abdominal Aortic Aneurysms J. Biasetti, F. Hussain, P.G. Spazzini and T.C. Gasser WCCM 2012 - 10th Word Congress on Computational Mechanics, S~aoPaulo, Brazil, July 8-13, 2012 (O) Growth of the small AAA: hemodynamic side J. Biasetti FAD Annual Scientific Meeting (Invited Talk), Madrid, Spain, May 3, 2012 (O) A fluido-chemical model to predict the growth of Intra-Luminal Thrombus in Abdominal Aortic Aneurysms J. Biasetti and T.C. Gasser ECCOMAS 2012 - 6th European Congress on Computational Methods in Applied Sciences and Engineering, Vienna, Austria, September 10-14, 2012 (O) The Intra-Luminal Thrombus in Abdominal Aortic Aneurysms: a fluid-chemical approach to model its development J. Biasetti, P.G. Spazzini, J. Swedenborg, F. Hussain and T.C. Gasser IMAD 2012 - 3rd International Meeting on Aortic Diseases, Liege, Belgium, October 4-6, 2012 (P) Contents Introduction 11 Background . 11 AAA Pathophysiology