The candidate is a trained fluid dynamics engineer who is addressing blood flow interactions with coronary stents. He will transition to experimental cardiovascular biomedicine under the """"""""Mentored Quantitative Research Development Award (K25)."""""""" Drug-eluting stents (DES) release anti-proliferative drugs that inhibit coronary restenosis. However, in 1% to 3% of DES recipients, late-stent thrombosis (LST) has emerged as a significant cause of morbidity and mortality up to several years post-stent deployment. Inhibition of restenosis retains the stent struts at or close to the arterial luminal surface and i contact with the flowing blood. I propose that the presence of a stent perturbs the near-wall hemodynamics and that the flow characteristics stimulate highly localized prothrombotic mechanisms. I have demonstrated by computational fluid dynamics that current commercial stents create local flow separations that are predicted to greatly favor prothrombotic conditions. This K25 research grant proposes topographic solutions to mitigate or eliminate flow separations and tests them by experiments under controlled conditions in vitro, a necessary set of proof-of-principle studies that arise from the computational analyses and precede experiments in vivo. I propose that the following conditions significantly promote LST: (i) increased residence time of coagulation elements, (ii) the induction of a prothrombotic endothelial phenotype where endothelium is still intact, and (iii) inhibition of protective re-endothelialization. My computational models of stent strut geometries that incorporate aerodynamic design (streamlining) predict the elimination of flow separation in the vicinity of the stent struts. I propose to validate the computational results experimentally to show that a streamlined stent geometry is conducive for re-endothelialization, promotion of atheroprotective endothelial phenotypes, and reduced propensity for thrombosis.
Aim 1 will test the hypothesis that flow in the vicinity of stent struts is highly influenced by strut geometry. Lasers and Partice Image Velocimetry (PIV) will be used to quantify flow disturbances in coronary artery hemodynamic conditions.
Aim 2 will address the hypothesis that pulsatile flow characteristics in the vicinity of streamlined and conventional stent strut geometries influences endothelial cell phenotype and re-endothelialization potential.
Aim 3 will study the transport of coagulation elements and platelets in the vicinity of stent struts using platelet rich plasma and whole blood t test the hypothesis that streamlining, regardless of bulk flow direction, promotes dilution of coagulation elements. The proposal addresses the mechanisms of an important clinical problem by exploring the potential high utility of stent re-design built upon our extensive experience in hemodynamics, biomedical engineering and vascular cell and molecular pathology.
Late stent thrombosis is a significant complication encountered after coronary artery stent deployment, the current preferred treatment for angina and heart attack. My project proposes that the physical shape of current commercial stent struts creates a blood flow environment that promotes inflammation and thrombosis, while a streamlined stent strut geometry can be incorporated into commercial stents to reduce or eliminate flow disturbances with a predicted decrease in thrombosis risk and improved clinical outcome. This important hemodynamics hypothesis related to current stent design will be tested and the underlying vascular mechanisms investigated, an essential experimental bridge to preclinical testing in an animal model and eventual successful implementation to improve the clinical efficacy of stents through the mitigation or elimination of late stent thrombosis.
|Davies, Peter F; Manduchi, Elisabetta; Jiménez, Juan M et al. (2017) Biofluids, cell mechanics and epigenetics: Flow-induced epigenetic mechanisms of endothelial gene expression. J Biomech 50:3-10|
|Jiang, Yi-Zhou; Manduchi, Elisabetta; Jiménez, Juan M et al. (2015) Endothelial epigenetics in biomechanical stress: disturbed flow-mediated epigenomic plasticity in vivo and in vitro. Arterioscler Thromb Vasc Biol 35:1317-26|
|Sweet, Daniel T; Jiménez, Juan M; Chang, Jeremy et al. (2015) Lymph flow regulates collecting lymphatic vessel maturation in vivo. J Clin Invest 125:2995-3007|
|Jiménez, Juan M; Prasad, Varesh; Yu, Michael D et al. (2014) Macro- and microscale variables regulate stent haemodynamics, fibrin deposition and thrombomodulin expression. J R Soc Interface 11:20131079|
|Jiang, Yi-Zhou; Jiménez, Juan M; Ou, Kristy et al. (2014) Hemodynamic disturbed flow induces differential DNA methylation of endothelial Kruppel-Like Factor 4 promoter in vitro and in vivo. Circ Res 115:32-43|
|Davies, Peter F; Manduchi, Elisabetta; Stoeckert, Christian J et al. (2014) Emerging topic: flow-related epigenetic regulation of endothelial phenotype through DNA methylation. Vascul Pharmacol 62:88-93|