title: Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure.
abstract: BACKGROUND
  Macrophages reside in the healthy myocardium, participate in ischemic heart disease, and modulate myocardial infarction (MI) healing. Their origin and roles in post-MI remodeling of nonischemic remote myocardium, however, remain unclear.
  
  
  OBJECTIVE
  This study investigated the number, origin, phenotype, and function of remote cardiac macrophages residing in the nonischemic myocardium in mice with chronic heart failure after coronary ligation.
  
  
  RESULTS
  Eight weeks post MI, fate mapping and flow cytometry revealed that a 2.9-fold increase in remote macrophages results from both increased local macrophage proliferation and monocyte recruitment. Heart failure produced by extensive MI, through activation of the sympathetic nervous system, expanded medullary and extramedullary hematopoiesis. Circulating Ly6C(high) monocytes rose from 64±5 to 108±9 per microliter of blood (P<0.05). Cardiac monocyte recruitment declined in Ccr2(-/-) mice, reducing macrophage numbers in the failing myocardium. Mechanical strain of primary murine and human macrophage cultures promoted cell cycle entry, suggesting that the increased wall tension in post-MI heart failure stimulates local macrophage proliferation. Strained cells activated the mitogen-activated protein kinase pathway, whereas specific inhibitors of this pathway reduced macrophage proliferation in strained cell cultures and in the failing myocardium (P<0.05). Steady-state cardiac macrophages, monocyte-derived macrophages, and locally sourced macrophages isolated from failing myocardium expressed different genes in a pattern distinct from the M1/M2 macrophage polarization paradigm. In vivo silencing of endothelial cell adhesion molecules curbed post-MI monocyte recruitment to the remote myocardium and preserved ejection fraction (27.4±2.4 versus 19.1±2%; P<0.05).
  
  
  CONCLUSIONS
  Myocardial failure is influenced by an altered myeloid cell repertoire.
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.). mnahrendorf@mgh.harvard.edu hendrik.sager@tum.de.
authors.forename: Hendrik B
authors.initials: HB
authors.lastname: Sager
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Maarten
authors.initials: M
authors.lastname: Hulsmans
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Kory J
authors.initials: KJ
authors.lastname: Lavine
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Marina B
authors.initials: MB
authors.lastname: Moreira
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Timo
authors.initials: T
authors.lastname: Heidt
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Gabriel
authors.initials: G
authors.lastname: Courties
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Benoit
authors.initials: B
authors.lastname: Tricot
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Omar F
authors.initials: OF
authors.lastname: Khan
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: James E
authors.initials: JE
authors.lastname: Dahlman
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Anna
authors.initials: A
authors.lastname: Borodovsky
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.).
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.affiliation: From the Center for Systems Biology, Department of Imaging (H.B.S., M.H., T.H., G.C., Y.S., Y.I., B.T., R.W., F.K.S., M.N.) and Cardiovascular Research Center (M.N.), Massachusetts General Hospital and Harvard Medical School, Boston; Center for Cardiovascular Research, Washington University School of Medicine, St Louis, MS (K.J.L.); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (M.B.M., P.L.); Department of Cardiology and Angiology I, Heart Center Freiburg University, Germany (T.H.); Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA (O.F.K., J.E.D., D.G.A.); David H. Koch Institute for Integrative Cancer Research (O.F.K., J.E.D., D.G.A.) and Department of Chemical Engineering (D.G.A.), Massachusetts Institute of Technology, Cambridge; Alnylam Pharmaceuticals, Cambridge, MA (A.B., K.F.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.). mnahrendorf@mgh.harvard.edu hendrik.sager@tum.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology*; D002478:Cells, Cultured; D002908:Chronic Disease; D005260:Female; D006333:Heart Failure / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology*
keywords: heart failure; hypertrophy; macrophage; monocyte; myocardial infarction