title: Spatial phenotyping of the endocardial endothelium as a function of intracardiac hemodynamic shear stress.
abstract: Despite substantial evidence for the central role of hemodynamic shear stress in the functional integrity of vascular endothelial cells, hemodynamic and molecular regulation of the endocardial endothelium lining the heart chambers remains understudied. We propose that regional differences in intracardiac hemodynamics influence differential endocardial gene expression leading to phenotypic heterogeneity of this cell layer. Measurement of intracardiac hemodynamics was performed using 4-dimensional flow MRI in healthy humans (n=8) and pigs (n=5). Local wall shear stress (WSS) and oscillatory shear indices (OSI) were calculated in three distinct regions of the LV - base, mid-ventricle (midV), and apex. In both the humans and pigs, WSS values were significantly lower in the apex and midV relative to the base. Additionally, both the apex and midV had greater oscillatory shear indices (OSI) than the base. To investigate regional phenotype, endocardial endothelial cells (EEC) were isolated from an additional 8 pigs and RNA sequencing was performed. A false discovery rate of 0.10 identified 1051 differentially expressed genes between the base and apex, and 321 between base and midV. Pathway analyses revealed apical upregulation of genes associated with translation initiation. Furthermore, tissue factor pathway inhibitor (TFPI; mean 50-fold) and prostacyclin synthase (PTGIS; 5-fold), genes prominently associated with antithrombotic protection, were consistently upregulated in LV apex. These spatio-temporal WSS values in defined regions of the left ventricle link local hemodynamics to regional heterogeneity in endocardial gene expression.
authors.affiliation: Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: memccorm72@gmail.com.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McCormick
authors.affiliation: Institute for Biomedical Informatics and Departments of, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Manduchi
authors.affiliation: Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Walter R T
authors.initials: WRT
authors.lastname: Witschey
authors.affiliation: Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gorman
authors.affiliation: Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Gorman
authors.affiliation: Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Yi-Zhou
authors.initials: YZ
authors.lastname: Jiang
authors.affiliation: Institute for Biomedical Informatics and Departments of, University of Pennsylvania, Philadelphia, PA, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Stoeckert
authors.affiliation: Departments of Radiology, Northwestern University, Chicago, IL, USA.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Barker
authors.affiliation: Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Yoon
authors.affiliation: Departments of Radiology, Northwestern University, Chicago, IL, USA; Department of Biomedical Engineering, Northwestern University, Chicago, IL, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Markl
authors.affiliation: Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Davies
mesh_terms: D000328:Adult; D000818:Animals; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000000981:diagnostic imaging / Q000502:physiology*; D005260:Female; D006352:Heart Ventricles / Q000000981:diagnostic imaging; D006439:Hemodynamics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D010641:Phenotype; D013314:Stress, Mechanical; D013552:Swine; D055815:Young Adult
keywords: 4D Flow MRI; Endocardial endothelium; Heart; RNA sequencing; Shear stress