Extent of flow recirculation governs expression of atherosclerotic and thrombotic biomarkers in arterial bifurcations.
OBJECTIVE
Atherogenesis, evolution of plaque, and outcomes following endovascular intervention depend heavily on the unique vascular architecture of each individual. Patient-specific, multiscale models able to correlate changes in microscopic cellular responses with relevant macroscopic flow, and structural conditions may help understand the progression of occlusive arterial disease, providing insights into how to mitigate adverse responses in specific settings and individuals.


RESULTS
Vascular architectures mimicking coronary and carotid bifurcations were derived from clinical imaging and used to generate conjoint computational meshes for in silico analysis and biocompatible scaffolds for in vitro models. In parallel with three-dimensional flow simulations, geometrically realistic scaffolds were seeded with human smooth muscle cells (SMC) or endothelial cells and exposed to relevant, physiological flows. In vitro surrogates of endothelial health, atherosclerotic progression, and thrombosis were locally quantified and correlated best with an quantified extent of flow recirculation occurring within the bifurcation models. Oxidized low-density lipoprotein uptake, monocyte adhesion, and tissue factor expression locally rose up to three-fold, and phosphorylated endothelial nitric oxide synthase and Krüppel-like factor 2 decreased up to two-fold in recirculation areas. Isolated testing in straight-tube idealized constructs subject to static, oscillatory, and pulsatile conditions, indicative of different recirculant conditions corroborated these flow-mediated dependencies.


CONCLUSIONS
Flow drives variations in vascular reactivity and vascular beds. Endothelial health was preserved by arterial flow but jeopardized in regions of flow recirculation in a quasi-linear manner. Similarly, SMC exposed to flow were more thrombogenic in large recirculating regions. Health, thrombosis, and atherosclerosis biomarkers correlate with the extent of recirculation in vascular cells lining certain vascular geometries.
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA Department of Chemical Engineering, IQS School of Engineering, URL, Via Augusta 390, 08017 Barcelona, Spain jordi.martorell@iqs.edu.
Jordi
J
Martorell
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA Department of Chemical Engineering, IQS School of Engineering, URL, Via Augusta 390, 08017 Barcelona, Spain.
Pablo
P
Santomá
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
Kumaran
K
Kolandaivelu
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA Charles Stark Draper Laboratory, Cambridge, MA, USA.
Vijaya B
VB
Kolachalama
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
Pedro
P
Melgar-Lesmes
Department of Chemical Engineering, IQS School of Engineering, URL, Via Augusta 390, 08017 Barcelona, Spain.
José J
JJ
Molins
Department of Interventional Cardiology and Vascular Medicine, St. Elizabeth's Medical Center, Boston, MA, USA.
Lawrence
L
Garcia
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Elazer R
ER
Edelman
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA Department of Biological Engineering, IQS School of Engineering, URL, Barcelona, Spain.
Mercedes
M
Balcells
D001158:Arteries / Q000473:pathology* / Q000503:physiopathology*; D050197:Atherosclerosis / Q000473:pathology / Q000503:physiopathology*; D015415:Biomarkers / Q000378:metabolism; D001696:Biomechanical Phenomena; D002339:Carotid Arteries / Q000473:pathology / Q000503:physiopathology; D003198:Computer Simulation; D003331:Coronary Vessels / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008955:Models, Cardiovascular; D032389:Myocytes, Smooth Muscle / Q000473:pathology / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D012039:Regional Blood Flow / Q000502:physiology; D013925:Thromboplastin / Q000378:metabolism; D013927:Thrombosis / Q000473:pathology / Q000503:physiopathology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D015415:Biomarkers; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D008077:Lipoproteins, LDL; D019010:Vascular Cell Adhesion Molecule-1; C099252:oxidized low density lipoprotein; D013925:Thromboplastin; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
Atherosclerosis; Endothelium; Flow; Geometry; Thrombosis