title: Integrated Regional Cardiac Hemodynamic Imaging and RNA Sequencing Reveal Corresponding Heterogeneity of Ventricular Wall Shear Stress and Endocardial Transcriptome.
abstract: BACKGROUND
  Unlike arteries, in which regionally distinct hemodynamics are associated with phenotypic heterogeneity, the relationships between endocardial endothelial cell phenotype and intraventricular flow remain largely unexplored. We investigated regional differences in left ventricular wall shear stress and their association with endocardial endothelial cell gene expression.
  
  
  RESULTS
  Local wall shear stress was calculated from 4-dimensional flow magnetic resonance imaging in 3 distinct regions of human (n=8) and pig (n=5) left ventricle: base, adjacent to the outflow tract; midventricle; and apex. In both species, wall shear stress values were significantly lower in the apex and midventricle relative to the base; oscillatory shear index was elevated in the apex. RNA sequencing of the endocardial endothelial cell transcriptome in pig left ventricle (n=8) at a false discovery rate ≤10% identified 1051 genes differentially expressed between the base and the apex and 327 between the base and the midventricle; no differentially expressed genes were detected at this false discovery rate between the apex and the midventricle. Enrichment analyses identified apical upregulation of genes associated with translation initiation including mammalian target of rapamycin, and eukaryotic initiation factor 2 signaling. Genes of mitochondrial dysfunction and oxidative phosphorylation were also consistently upregulated in the left ventricular apex, as were tissue factor pathway inhibitor (mean 50-fold) and prostacyclin synthase (5-fold)-genes prominently associated with antithrombotic protection.
  
  
  CONCLUSIONS
  We report the first spatiotemporal measurements of wall shear stress within the left ventricle and linked regional hemodynamics to heterogeneity in ventricular endothelial gene expression, most notably to translation initiation and anticoagulation properties in the left ventricular apex, in which oscillatory shear index is increased and wall shear stress is decreased.
authors.affiliation: Institute for Medicine and Engineering, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McCormick
authors.affiliation: Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Manduchi
authors.affiliation: Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Walter R T
authors.initials: WR
authors.lastname: Witschey
authors.affiliation: Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gorman
authors.affiliation: Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Gorman
authors.affiliation: Institute for Medicine and Engineering, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Yi-Zhou
authors.initials: YZ
authors.lastname: Jiang
authors.affiliation: Institute for Biomedical Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Stoeckert
authors.affiliation: Department of Radiology, Northwestern University, Chicago, IL.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Barker
authors.affiliation: Department of Radiology, Northwestern University, Chicago, IL Department of Biomedical Engineering, Northwestern University, Chicago, IL.
authors.forename: Michael
authors.initials: M
authors.lastname: Markl
authors.affiliation: Institute for Medicine and Engineering, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA pfd@mail.med.upenn.edu.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Davies
mesh_terms: D000818:Animals; D057791:Cardiac Imaging Techniques; D004699:Endocardium / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D015698:Genomic Library; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000378:metabolism*; D006439:Hemodynamics; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D012313:RNA / Q000235:genetics*; D033081:Shear Strength / Q000502:physiology*; D013552:Swine; D016277:Ventricular Function, Left / Q000502:physiology; D055815:Young Adult
chemical_list: D012313:RNA
keywords: 4‐dimensional flow magnetic resonance imaging; endocardium; gene expression; hemodynamics; ventricle