title: Manganese-Enhanced Magnetic Resonance Imaging Enables In Vivo Confirmation of Peri-Infarct Restoration Following Stem Cell Therapy in a Porcine Ischemia-Reperfusion Model.
abstract: BACKGROUND
  The exact mechanism of stem cell therapy in augmenting the function of ischemic cardiomyopathy is unclear. In this study, we hypothesized that increased viability of the peri-infarct region (PIR) produces restorative benefits after stem cell engraftment. A novel multimodality imaging approach simultaneously assessed myocardial viability (manganese-enhanced magnetic resonance imaging [MEMRI]), myocardial scar (delayed gadolinium enhancement MRI), and transplanted stem cell engraftment (positron emission tomography reporter gene) in the injured porcine hearts.
  
  
  RESULTS
  Twelve adult swine underwent ischemia-reperfusion injury. Digital subtraction of MEMRI-negative myocardium (intrainfarct region) from delayed gadolinium enhancement MRI-positive myocardium (PIR and intrainfarct region) clearly delineated the PIR in which the MEMRI-positive signal reflected PIR viability. Human amniotic mesenchymal stem cells (hAMSCs) represent a unique population of immunomodulatory mesodermal stem cells that restored the murine PIR. Immediately following hAMSC delivery, MEMRI demonstrated an increased PIR viability signal compared with control. Direct PIR viability remained higher in hAMSC-treated hearts for >6 weeks. Increased PIR viability correlated with improved regional contractility, left ventricular ejection fraction, infarct size, and hAMSC engraftment, as confirmed by immunocytochemistry. Increased MEMRI and positron emission tomography reporter gene signal in the intrainfarct region and the PIR correlated with sustained functional augmentation (global and regional) within the hAMSC group (mean change, left ventricular ejection fraction: hAMSC 85±60%, control 8±10%; P<0.05) and reduced chamber dilatation (left ventricular end-diastole volume increase: hAMSC 24±8%, control 110±30%; P<0.05).
  
  
  CONCLUSIONS
  The positron emission tomography reporter gene signal of hAMSC engraftment correlates with the improved MEMRI signal in the PIR. The increased MEMRI signal represents PIR viability and the restorative potential of the injured heart. This in vivo multimodality imaging platform represents a novel, real-time method of tracking PIR viability and stem cell engraftment while providing a mechanistic explanation of the therapeutic efficacy of cardiovascular stem cells.
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA (R.D., P.J.K., Y.M., F.I., S.M., N.F.H., J.K.L., P.K.N., X.G., M.V.M.C., J.C.W., A.C.Y., P.C.Y.) Stanford Cardiovascular Institute, Stanford University, Stanford, CA (R.D., N.F.H., P.K.N., M.V.M.C., J.C.W., P.C.Y.).
authors.forename: Rajesh
authors.initials: R
authors.lastname: Dash
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA (R.D., P.J.K., Y.M., F.I., S.M., N.F.H., J.K.L., P.K.N., X.G., M.V.M.C., J.C.W., A.C.Y., P.C.Y.).
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kim
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA (R.D., P.J.K., Y.M., F.I., S.M., N.F.H., J.K.L., P.K.N., X.G., M.V.M.C., J.C.W., A.C.Y., P.C.Y.).
authors.forename: Yuka
authors.initials: Y
authors.lastname: Matsuura
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA (R.D., P.J.K., Y.M., F.I., S.M., N.F.H., J.K.L., P.K.N., X.G., M.V.M.C., J.C.W., A.C.Y., P.C.Y.).
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ikeno
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA (R.D., P.J.K., Y.M., F.I., S.M., N.F.H., J.K.L., P.K.N., X.G., M.V.M.C., J.C.W., A.C.Y., P.C.Y.).
authors.forename: Scott
authors.initials: S
authors.lastname: Metzler
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA (R.D., P.J.K., Y.M., F.I., S.M., N.F.H., J.K.L., P.K.N., X.G., M.V.M.C., J.C.W., A.C.Y., P.C.Y.) Stanford Cardiovascular Institute, Stanford University, Stanford, CA (R.D., N.F.H., P.K.N., M.V.M.C., J.C.W., P.C.Y.).
authors.forename: Ngan F
authors.initials: NF
authors.lastname: Huang
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA (R.D., P.J.K., Y.M., F.I., S.M., N.F.H., J.K.L., P.K.N., X.G., M.V.M.C., J.C.W., A.C.Y., P.C.Y.).
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Lyons
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA (R.D., P.J.K., Y.M., F.I., S.M., N.F.H., J.K.L., P.K.N., X.G., M.V.M.C., J.C.W., A.C.Y., P.C.Y.) Stanford Cardiovascular Institute, Stanford University, Stanford, CA (R.D., N.F.H., P.K.N., M.V.M.C., J.C.W., P.C.Y.).
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Nguyen
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA (R.D., P.J.K., Y.M., F.I., S.M., N.F.H., J.K.L., P.K.N., X.G., M.V.M.C., J.C.W., A.C.Y., P.C.Y.).
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Ge
authors.affiliation: Biocardia Inc, San Carlos, CA (C.W.P.F.).
authors.forename: Cheryl Wong Po
authors.initials: CW
authors.lastname: Foo
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA (R.D., P.J.K., Y.M., F.I., S.M., N.F.H., J.K.L., P.K.N., X.G., M.V.M.C., J.C.W., A.C.Y., P.C.Y.) Department of Electrical Engineering, Stanford University, Stanford, CA (M.V.M.C.) Stanford Cardiovascular Institute, Stanford University, Stanford, CA (R.D., N.F.H., P.K.N., M.V.M.C., J.C.W., P.C.Y.).
authors.forename: Michael V
authors.initials: MV
authors.lastname: McConnell
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA (R.D., P.J.K., Y.M., F.I., S.M., N.F.H., J.K.L., P.K.N., X.G., M.V.M.C., J.C.W., A.C.Y., P.C.Y.) Stanford Cardiovascular Institute, Stanford University, Stanford, CA (R.D., N.F.H., P.K.N., M.V.M.C., J.C.W., P.C.Y.).
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA (R.D., P.J.K., Y.M., F.I., S.M., N.F.H., J.K.L., P.K.N., X.G., M.V.M.C., J.C.W., A.C.Y., P.C.Y.).
authors.forename: Alan C
authors.initials: AC
authors.lastname: Yeung
authors.affiliation: Eagle Vision Pharmaceutical Corp, Downingtown, PA (P.H.).
authors.forename: Phillip
authors.initials: P
authors.lastname: Harnish
authors.affiliation: Division of Cardiovascular Medicine, Stanford University, Stanford, CA (R.D., P.J.K., Y.M., F.I., S.M., N.F.H., J.K.L., P.K.N., X.G., M.V.M.C., J.C.W., A.C.Y., P.C.Y.) Stanford Cardiovascular Institute, Stanford University, Stanford, CA (R.D., N.F.H., P.K.N., M.V.M.C., J.C.W., P.C.Y.).
authors.forename: Phillip C
authors.initials: PC
authors.lastname: Yang
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D004195:Disease Models, Animal; D005682:Gadolinium; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008345:Manganese; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D009206:Myocardium / Q000473:pathology; D049268:Positron-Emission Tomography; D015427:Reperfusion Injury / Q000628:therapy*; D013234:Stem Cells / Q000502:physiology; D013552:Swine; D014022:Tissue Survival; D014057:Tomography, X-Ray Computed; D016277:Ventricular Function, Left / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D008345:Manganese; D005682:Gadolinium
keywords: ischemia–reperfusion injury; magnetic resonance imaging; manganese‐enhanced magnetic resonance imaging; peri‐infarct region imaging; stem cell imaging