Assessment of predicting blood flow and atherosclerosis in the aorta and renal arteries by Alexander Fuchs August 2020 Technical Reports KTH Royal Institute of Technology Department of Engineering Mechanics SE-100 44 Stockholm, Sweden 1 Akademisk avhandling som med tillstånd av Kungliga Tekniska högskolan framlägges till offentlig granskning för avläggande av teknologie doktorsexamen fredagen den 28:e augusti 2020 klockan 14:00 i Sal F3, Lindstedtsvägen 26, Stockholm ISBN: 978-91-7873-585-3 TRITA-SCI-FOU 2020:23 Cover: Time-averaged Wall Shear-Stress (TAWSS) distribution over a human aorta and in the main arteries branching from the thoracic and abdominal aorta. Heart-rate 60 BPM (beats per minute) and cardiac output of 5 LPM (liters per minute). © Fuchs Alexander Tryck: Universitetsservice US AB, 2020 2 To Louise, Gunnar and Bernard 3 Assessment of predicting blood flow and atherosclerosis in the aorta and renal arteries Alexander Fuchs KTH, Dept. Engineering Mechanics Abstract Cardiovascular diseases (CVD) are the most common cause of death in large parts of the world. Atherosclerosis (AS) has a major part in most CVDs. AS is a slowly developing disease which is dependent on multiple factors such as genetics and life style (food, smoking, and physical activities). AS is primarily a disease of the arterial wall and develops preferentially at certain locations (such as arterial branches and in certain vessels like the coronary arteries). The close relation between AS sites and blood flow has been well established over the years. However, due to multi-factorial causes, there exist no early prognostic tools for identifying individuals that should be treated prophylactically or followed up. The underlying hypothesis of this thesis was to determine if it is possible to use blood flow simulations of patient-specific cases in order to identify individuals with risk for developing AS. CT scans from patients with renal artery stenosis (RAS) were used to get the affected vessels geometry. Blood flow in original and “reconstructed” arteries were simulated. Commonly used wall shear stress (WSS) related indicators of AS were studied to assess their use as risk indicators for developing AS. Divergent results indicated urgent need to assess the impact of simulation related factors on results. Altogether, blood flow in the following vessels was studied: The whole aorta with branches from the aortic arch and the abdominal aorta, abdominal aorta as well as the renal arteries, and separately the thoracic aorta with the three main branching arteries from the aortic arch. The impact of geometrical reconstruction, employed boundary conditions (BCs), effects of flow-rate, heart-rate and models of blood viscosity as function of local hematocrit (red blood cell, RBC, concentration) and shear-rate were studied in some detail. In addition to common WSS-related indicators, we suggested the use of endothelial activation models as a further risk indicator. The simulations data was used to extract not only the WSS-related data but also the impact of flow-rate on the extent of retrograde flow in the aorta and close to its walls. The formation of helical motion and flow instabilities (which at high flow- and heart-rate lead to turbulence) was also considered. Results A large number of simulations (more than 100) were carried out. These simulations assessed the use of flow-rate specified BCs, pressure based BCs or so called windkessel (WK) outlet BCs that simulate effects of peripheral arterial compliance. The results showed high sensitivity of the flow to BCs. For example, the deceleration phase of the flow-rate is more prone to flow instabilities (as also expressed in terms of multiple inflection points in the streamwise velocity profile) as well as leading to retrograde flow. In contrast, the acceleration phase leads to uni-directional and more stable flow. As WSS unsteadiness was found to be pro-AS, it was important to assess the effect flow-rate deceleration, under physiological and pathological conditions. Peaks of retrograde flow occur at local temporal minima in flow-rate. WK BCs require ad-hoc adjusted parameters and are therefore useful only when fully patient 4 specific (i.e. all information is valid for a particular patient at a particular point of time) data is available. Helical flows which are considered as atheroprotective, are formed naturally, depending primarily on the geometry (due to the bends in the thoracic aorta). Helical flow was also observed in the major aortic branches. The helical motion is weaker during flow deceleration and diastole when it may locally also change direction. Most common existing blood viscosity models are based on hematocrit and shear-rate. These models show strong variation of blood (mixture) viscosity. With strong shear-rate blood viscosity is lowest and is almost constant. The impact of blood viscosity in terms of dissipation is counter balanced by the shear-rate; At low shear-rate the blood has larger viscosity and at high shear-rate it is the opposite. This effect and due to the temporal variations in the local flow conditions the effect of blood rheology on the WSS indicators is weak. Tracking of blood components and clot-models shows that the retrograde motion and the flow near branches may have so strong curvature that centrifugal force can become important. This effect may lead to the transport of a thrombus from the descending aorta back to the branches of the aortic arch and could cause embolic stroke. The latter results confirm clinical observation of the risk of stroke due to transport of emboli from the proximal part of the descending aorta upstream to the vessels branching from the aortic arch and which lead blood to the brain. Conclusions The main reasons for not being able to propose an early predictive tool for future development of AS are four-folded: i. At present, the mechanisms behind AS are not adequately understood to enable to define a set of parameters that are sensitive and specific enough to be predictive of its development. ii. The lack of accurate patient-specific data (BCs) over the whole physiological “envelop” allows only limited number of flow simulations which may not be adequate for patient- specific predictive purposes. iii. The shortcomings of current models with respect to material properties of blood and arterial walls (for patient-specific space- and time-variations) are lacking. iv. There is a need for better simulation data processing, i.e. tools that enable deducing general predictive atherosclerotic parameters from a limited number of simulations, through e.g. extending reduced modeling and/or deep learning. The results do show, however, that blood flow simulations may produce very useful data that enhances understanding of clinically observed processes such as explaining helical- and retrograde flows and the transport of blood components and emboli in larger arteries. Key words: Blood flow simulations, Atherosclerosis, Wall shear stress (WSS), blood rheology models 5 Sammanfattning Hjärt- och kärlsjukdomar är den vanligaste dödsorsaken i stora delar av världen. Åderförkalkning (atheroscleros) spelar betydande roll för denna grupp av sjukdomar. Åderförkalkning utvecklas under lång tid och beror på många olika faktorer såsom genetiska och livsstilsrelaterade (exempelvis kost, rökning och fysisk aktivitet). Åderförkalkning drabbar blodkärlens, artärernas, väggar och formas oftare på vissa lokaler än andra (t ex vid kärlförgreningar och i särsklida kärl som exempelvis hjärtats kranskärl). Det nära sambandet mellan blodflöde och åderförkalkning är väl etablerat sedan många år. P.g.a. den multifaktoriella genesen existerar inget tillförlitligt test för att tidigt upptäcka individer i behov av förebyggande behandling eller uppföljning vid atherosclerotisk hjärt- och kärlsjukdom. Den bakomliggande hypotesen för denna avhandling var att bestämma om blodflödessimuleringar i patient-specifika fall kan identifiera risk för atherosclerosutveckling. Datortomografiundersökningar från patienter med njurartärstenos användes för att framställa blodkärlens utseende (geometri). Blodflödet simulerades i de drabbade kärlen samt efter att de ”rekonstruerats till originalskick”. Vanligt använda indikatorer baserade på väggskjuvspänningen (VSS) studerades för att bedöma risk för atherosclerosutveckling. Bitvis spretiga resultat visade på stort behov att bedöma känsligheten för simuleringsberoende faktorer. Blodflödet har huvudsakligen studerats i hela stora kroppsålderna (aorta) inklusive dess stora grenar i bröstkorgen och buken, bröstkorgens aorta med tre stora tillhörande grenar samt bukaorta inklusive njurartärerna. Inverkan av kärlgeometrin, dess rekontruktion, randvillkor, hjärt-minut-volym, puls och blodets viskositet (den sistnämnda beroende på röda blodkropparnas volymfraktion (hematokrit) och den lokala skjuvhastigheten) studerades. Utöver vanligen använda VSS-baserade parameter har även modeller för aktivering av endotelceller prövats som riskindikator för åderförkalkning. Därtill användes resultaten från simuleringarna till att kvantifiera backflöde (både inne i aorta och vid dess vägg). Förekomst av helikalt (spiralformat) flöde och instabiliteter (vilka leder till turbulens vid hög puls och hjärt-minut-volym) betraktades också. Resultat: Ett stort antal simuleringar (över 100) har utförts. Utvärdering har gjorts av flödesspecifika randvillkor, blodtryckbaserade randvillkor och s.k. ”windkessel (WK)”-randvillkor på kärlens utlopp för att simulera effekterna av kärlträdets