Are Computer Simulations Misleading Us About the Pathobiology of Cerebrovascular Diseases?

Stroke is one of the leading causes of death worldwide often caused by defect balloon-shaped blood vessels in the brain (aneurysms). Aneurysms are focally distributed, which highlights the role of blood flow-induced wall shear stress. Direct measurements of these stresses are difficult and medical image-based computational fluid dynamics (CFD) has been extensively used to study the 'patient-specific' local abnormal forces in search for a mechanistic biological link to disease initiation. However, while robust, the default settings in most commercial codes trade accuracy for speed, and are generally incapable of handling complex flows. The principal investigator (PI) has previously shown that such commercial tools can be misleading about the nature of flow in the cardiovascular system, overlooking a flow phenotype called 'turbulence'. Therefore, in the current project, we have developed novel and sophisticated numerical tools that can simulate both turbulent flows and fluid structure interactions. These tools were further used to demonstrate that vascular walls may vibrate under certain circumstances. We showed that these vibrations might be relatively common in vascular pathologies and hypothesized about the mechanobiological relevance. We further showed that there is an association between turbulence-induced fluctuations and presence of aneurysms in patients with an aneurysm on one side of the brain where the other side was used as control. High-fidelity simulation results were then used to guide laboratory experiments on endothelial cells. The cells shifted towards a dysfunctional phenotype when exposed to vibrations associated with turbulent-like flows, which led to increased permeability. The latter might shed light on fundamental properties of the vascular system.

I dette prosjektet har vi utviklet nye numeriske verktøy med unike egenskaper som er fritt tilgjengelige. Vi har brukt disse til å vise fundamentale egenskaper ved karsystemet, nemlig høyfrekvente vibrasjoner ved enkelte sykdommer. På kort sikt har disse resultatene vist seg å være svært kontroversielle, men de er også godt dokumentert. Mest av alt har det tiltrukket seg oppmerksomhet fra utenlandske forskingsmiljøer som prosjektlederen har knyttet sterke bånd til og startet nye samarbeidsprosjekter med. På litt lengre sikt kan vi muligens forvente oss et paradigmeskifte der vi ikke bare studerer krefter på åreveggen, men også på dynamiske krefter som virker i selve veggen.

Stroke is one of the leading causes of death worldwide caused by either atherosclerotic plaques or defect balloon-shaped blood vessels in the brain (aneurysms). Both diseases are focally distributed, which highlights the role of blood flow-induced wall shear stress. Direct measurements of these stresses are difficult and medical image-based computational fluid dynamics (CFD) has been extensively used to study the 'patient-specific' local abnormal forces in search for a mechanistic biological link to disease initiation. However, while robust, the default settings in most commercial codes trade accuracy for speed, and are generally incapable of handling complex flows. The principal investigator (PI) has previously shown that such commercial tools can be misleading about the nature of flow in the cardiovascular system. The PI's ambition is to holistically answer fundamental questions in vascular biology critical for our understanding of disease initiation, which can ultimately pave the way for prevention or reversal of the disease. The key innovation is development of novel and sophisticated numerical models to test hypotheses in biomechanics and to guide in vitro cell experiments. These experiments will elucidate the role of turbulent-like flows in endothelial phenotype and the frequency spectrum that endothelial cells can sense, distinguish, and finally respond via phenotype shifting. Since aneurysms normally only occurs at one side of the blood vessels in the brain, we will investigate whether there are in vivo differences in flow phenotypes at the aneurysmal side. These experiments will rule out any patient genetic predisposition and effects of systemic risk factors allowing for investigation of hemodynamic effects on aneurysm initiation and development. This unique set of in silico, in vitro, and in vivo experiments will authoritatively elucidate the role of hemodynamic instabilities in aneurysm initiation.