title: FDG-PET reveals improved cardiac regeneration and attenuated adverse remodelling following Sitagliptin + G-CSF therapy after acute myocardial infarction.
abstract: OBJECTIVE
  Dual therapy comprising G-CSF for mobilization of bone marrow-derived progenitor cells (BMPCs), with simultaneous pharmacological inhibition of dipeptidylpeptidase-IV for enhanced myocardial recruitment of circulating BMPC via the SDF-1α/CXCR4-axis, has been shown to improve survival after acute myocardial infarction (AMI). Using an innovative method to provide non-invasive serial in vivo measurements and information on metabolic processes, we aimed to substantiate the possible effects of this therapeutic concept on cardiac remodelling after AMI using 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography (FDG-PET).
  
  
  RESULTS
  AMI was induced in C57BL/6 mice by performing surgical ligation of the left anterior descending artery in these mice. Animals were then treated with granulocyte-colony stimulating factor + Sitagliptin (GS) or placebo for a duration of 5 days following AMI. From serial PET scans, we verified that the infarct size in GS-treated mice (n = 13) was significantly reduced at Day 30 after AMI when compared with the mice receiving placebo (n = 10). Analyses showed a normalized FDG uptake on Day 6 in GS-treated mice, indicating an attenuation of the cardiac inflammatory response to AMI in treated animals. Furthermore, flow cytometry showed a significant increase in the anti-inflammatory M2-macrophages subpopulation in GS-treated animals. In comparing GS treated with placebo animals, those receiving GS-therapy showed a reduction in myocardial hypertrophy and left ventricular dilatation, which indicates the beneficial effect of GS treatment on cardiac remodelling. Remarkably, flow cytometry and immunohistochemistry showed an increase of myocardial c-kit positive cells in treated mice (n = 12 in both groups).
  
  
  CONCLUSIONS
  Using the innovative method of micro-PET for non-invasive serial in vivo measurements of metabolic myocardial processes in mice, we were able to provide mechanistic evidence that GS therapy improves cardiac regeneration and reduces adverse remodelling after AMI.
authors.affiliation: Department of Cardiology, Ludwig-Maximilians-University, Marchioninistrasse 15, Munich 81377, Germany lisa.gross@med.uni-muenchen.de.
authors.forename: Lisa
authors.initials: L
authors.lastname: Gross
authors.affiliation: Department of Cardiology, Ludwig-Maximilians-University, Marchioninistrasse 15, Munich 81377, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Paintmayer
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lehner
authors.affiliation: Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Brandl
authors.affiliation: Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Brenner
authors.affiliation: Department of Cardiology, Ludwig-Maximilians-University, Marchioninistrasse 15, Munich 81377, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grabmaier
authors.affiliation: Department of Cardiology, Ludwig-Maximilians-University, Marchioninistrasse 15, Munich 81377, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Huber
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bartenstein
authors.affiliation: Department of Cardiology, Ludwig-Maximilians-University, Marchioninistrasse 15, Munich 81377, Germany.
authors.forename: Hans-Diogenes
authors.initials: HD
authors.lastname: Theiss
authors.affiliation: Department of Internal Medicine III, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Wolfgang-Michael
authors.initials: WM
authors.lastname: Franz
authors.affiliation: Department of Cardiology, Ludwig-Maximilians-University, Marchioninistrasse 15, Munich 81377, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Andrei
authors.initials: A
authors.lastname: Todica
authors.affiliation: Department of Cardiology, Ludwig-Maximilians-University, Marchioninistrasse 15, Munich 81377, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Brunner
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D019788:Fluorodeoxyglucose F18; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals; D012038:Regeneration / Q000187:drug effects; D000068900:Sitagliptin Phosphate / Q000494:pharmacology*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D016179:Granulocyte Colony-Stimulating Factor; D000068900:Sitagliptin Phosphate
keywords: C-kit; G-CSF; Sitagliptin; acute myocardial infarction; cardiac remodelling; positron emission tomography