title: Natural IgM Blockade Limits Infarct Expansion and Left Ventricular Dysfunction in a Swine Myocardial Infarct Model.
abstract: BACKGROUND
  Acute coronary syndrome is the leading cause of mortality worldwide. However, treatment of acute coronary occlusion inevitably results in ischemia-reperfusion injury. Circulating natural IgM has been shown to play a significant role in mouse models of ischemia-reperfusion injury. A highly conserved self-antigen, nonmuscle myosin heavy chain II, has been identified as a target of pathogenic IgM. We hypothesized that a monoclonal antibody (m21G6) directed against nonmuscle myosin heavy chain II may inhibit IgM binding and reduce injury in a preclinical model of myocardial infarction. Thus, our objective was to evaluate the efficacy of intravenous m21G6 treatment in limiting infarct expansion, troponin release, and left ventricular dysfunction in a swine myocardial infarction model.
  
  
  RESULTS
  Massachusetts General Hospital miniature swine underwent occlusion of the midleft anterior descending coronary artery for 60 minutes, followed by 1 hour, 5-day, or 21-day reperfusion. Specificity and localization of m21G6 to injured myocardium were confirmed using fluorescently labeled m21G6. Treatment with m21G6 before reperfusion resulted in a 49% reduction in infarct size (P<0.005) and a 61% reduction in troponin-T levels (P<0.05) in comparison with saline controls at 5-day reperfusion. Furthermore, m21G6-treated animals recovered 85.4% of their baseline left ventricular function as measured by 2-dimensional transthoracic echocardiography in contrast to 67.1% in controls at 21-day reperfusion (P<0.05).
  
  
  CONCLUSIONS
  Treatment with m21G6 significantly reduced infarct size and troponin-T release, and led to marked preservation of cardiac function in our study. Overall, these findings suggest that pathogenic IgM blockade represents a valid therapeutic strategy in mitigating myocardial ischemia-reperfusion injury.
authors.affiliation: From the Transplantation Biology Research Center, Massachusetts General Hospital, Charlestown (S.S., J.D.G., J.C.M., D.H.S., J.S.A.); Cardiac Surgery Research Laboratory, Massachusetts General Hospital, Boston, (J.L.G., J.B., J.S.A.); DecImmune Therapeutics, Cambridge, MA (M.S.H., E.M.A., F.S., R.J.P., W.N.); Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA (M.C.C.); Department of Pediatrics, Harvard Medical School, Boston, MA (M.C.C.); and Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia (K.M.K.).
authors.forename: Smita
authors.initials: S
authors.lastname: Sihag
authors.affiliation: From the Transplantation Biology Research Center, Massachusetts General Hospital, Charlestown (S.S., J.D.G., J.C.M., D.H.S., J.S.A.); Cardiac Surgery Research Laboratory, Massachusetts General Hospital, Boston, (J.L.G., J.B., J.S.A.); DecImmune Therapeutics, Cambridge, MA (M.S.H., E.M.A., F.S., R.J.P., W.N.); Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA (M.C.C.); Department of Pediatrics, Harvard Medical School, Boston, MA (M.C.C.); and Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia (K.M.K.).
authors.forename: Michael S
authors.initials: MS
authors.lastname: Haas
authors.affiliation: From the Transplantation Biology Research Center, Massachusetts General Hospital, Charlestown (S.S., J.D.G., J.C.M., D.H.S., J.S.A.); Cardiac Surgery Research Laboratory, Massachusetts General Hospital, Boston, (J.L.G., J.B., J.S.A.); DecImmune Therapeutics, Cambridge, MA (M.S.H., E.M.A., F.S., R.J.P., W.N.); Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA (M.C.C.); Department of Pediatrics, Harvard Medical School, Boston, MA (M.C.C.); and Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia (K.M.K.).
authors.forename: Karen M
authors.initials: KM
authors.lastname: Kim
authors.affiliation: From the Transplantation Biology Research Center, Massachusetts General Hospital, Charlestown (S.S., J.D.G., J.C.M., D.H.S., J.S.A.); Cardiac Surgery Research Laboratory, Massachusetts General Hospital, Boston, (J.L.G., J.B., J.S.A.); DecImmune Therapeutics, Cambridge, MA (M.S.H., E.M.A., F.S., R.J.P., W.N.); Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA (M.C.C.); Department of Pediatrics, Harvard Medical School, Boston, MA (M.C.C.); and Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia (K.M.K.).
authors.forename: J Luis
authors.initials: JL
authors.lastname: Guerrero
authors.affiliation: From the Transplantation Biology Research Center, Massachusetts General Hospital, Charlestown (S.S., J.D.G., J.C.M., D.H.S., J.S.A.); Cardiac Surgery Research Laboratory, Massachusetts General Hospital, Boston, (J.L.G., J.B., J.S.A.); DecImmune Therapeutics, Cambridge, MA (M.S.H., E.M.A., F.S., R.J.P., W.N.); Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA (M.C.C.); Department of Pediatrics, Harvard Medical School, Boston, MA (M.C.C.); and Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia (K.M.K.).
authors.forename: Jonathan
authors.initials: J
authors.lastname: Beaudoin
authors.affiliation: From the Transplantation Biology Research Center, Massachusetts General Hospital, Charlestown (S.S., J.D.G., J.C.M., D.H.S., J.S.A.); Cardiac Surgery Research Laboratory, Massachusetts General Hospital, Boston, (J.L.G., J.B., J.S.A.); DecImmune Therapeutics, Cambridge, MA (M.S.H., E.M.A., F.S., R.J.P., W.N.); Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA (M.C.C.); Department of Pediatrics, Harvard Medical School, Boston, MA (M.C.C.); and Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia (K.M.K.).
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Alicot
authors.affiliation: From the Transplantation Biology Research Center, Massachusetts General Hospital, Charlestown (S.S., J.D.G., J.C.M., D.H.S., J.S.A.); Cardiac Surgery Research Laboratory, Massachusetts General Hospital, Boston, (J.L.G., J.B., J.S.A.); DecImmune Therapeutics, Cambridge, MA (M.S.H., E.M.A., F.S., R.J.P., W.N.); Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA (M.C.C.); Department of Pediatrics, Harvard Medical School, Boston, MA (M.C.C.); and Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia (K.M.K.).
authors.forename: Franziska
authors.initials: F
authors.lastname: Schuerpf
authors.affiliation: From the Transplantation Biology Research Center, Massachusetts General Hospital, Charlestown (S.S., J.D.G., J.C.M., D.H.S., J.S.A.); Cardiac Surgery Research Laboratory, Massachusetts General Hospital, Boston, (J.L.G., J.B., J.S.A.); DecImmune Therapeutics, Cambridge, MA (M.S.H., E.M.A., F.S., R.J.P., W.N.); Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA (M.C.C.); Department of Pediatrics, Harvard Medical School, Boston, MA (M.C.C.); and Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia (K.M.K.).
authors.forename: James D
authors.initials: JD
authors.lastname: Gottschall
authors.affiliation: From the Transplantation Biology Research Center, Massachusetts General Hospital, Charlestown (S.S., J.D.G., J.C.M., D.H.S., J.S.A.); Cardiac Surgery Research Laboratory, Massachusetts General Hospital, Boston, (J.L.G., J.B., J.S.A.); DecImmune Therapeutics, Cambridge, MA (M.S.H., E.M.A., F.S., R.J.P., W.N.); Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA (M.C.C.); Department of Pediatrics, Harvard Medical School, Boston, MA (M.C.C.); and Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia (K.M.K.).
authors.forename: Robyn J
authors.initials: RJ
authors.lastname: Puro
authors.affiliation: From the Transplantation Biology Research Center, Massachusetts General Hospital, Charlestown (S.S., J.D.G., J.C.M., D.H.S., J.S.A.); Cardiac Surgery Research Laboratory, Massachusetts General Hospital, Boston, (J.L.G., J.B., J.S.A.); DecImmune Therapeutics, Cambridge, MA (M.S.H., E.M.A., F.S., R.J.P., W.N.); Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA (M.C.C.); Department of Pediatrics, Harvard Medical School, Boston, MA (M.C.C.); and Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia (K.M.K.).
authors.forename: Joren C
authors.initials: JC
authors.lastname: Madsen
authors.affiliation: From the Transplantation Biology Research Center, Massachusetts General Hospital, Charlestown (S.S., J.D.G., J.C.M., D.H.S., J.S.A.); Cardiac Surgery Research Laboratory, Massachusetts General Hospital, Boston, (J.L.G., J.B., J.S.A.); DecImmune Therapeutics, Cambridge, MA (M.S.H., E.M.A., F.S., R.J.P., W.N.); Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA (M.C.C.); Department of Pediatrics, Harvard Medical School, Boston, MA (M.C.C.); and Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia (K.M.K.).
authors.forename: David H
authors.initials: DH
authors.lastname: Sachs
authors.affiliation: From the Transplantation Biology Research Center, Massachusetts General Hospital, Charlestown (S.S., J.D.G., J.C.M., D.H.S., J.S.A.); Cardiac Surgery Research Laboratory, Massachusetts General Hospital, Boston, (J.L.G., J.B., J.S.A.); DecImmune Therapeutics, Cambridge, MA (M.S.H., E.M.A., F.S., R.J.P., W.N.); Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA (M.C.C.); Department of Pediatrics, Harvard Medical School, Boston, MA (M.C.C.); and Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia (K.M.K.).
authors.forename: Walter
authors.initials: W
authors.lastname: Newman
authors.affiliation: From the Transplantation Biology Research Center, Massachusetts General Hospital, Charlestown (S.S., J.D.G., J.C.M., D.H.S., J.S.A.); Cardiac Surgery Research Laboratory, Massachusetts General Hospital, Boston, (J.L.G., J.B., J.S.A.); DecImmune Therapeutics, Cambridge, MA (M.S.H., E.M.A., F.S., R.J.P., W.N.); Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA (M.C.C.); Department of Pediatrics, Harvard Medical School, Boston, MA (M.C.C.); and Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia (K.M.K.).
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
authors.affiliation: From the Transplantation Biology Research Center, Massachusetts General Hospital, Charlestown (S.S., J.D.G., J.C.M., D.H.S., J.S.A.); Cardiac Surgery Research Laboratory, Massachusetts General Hospital, Boston, (J.L.G., J.B., J.S.A.); DecImmune Therapeutics, Cambridge, MA (M.S.H., E.M.A., F.S., R.J.P., W.N.); Program in Cellular and Molecular Medicine, Boston Children's Hospital, MA (M.C.C.); Department of Pediatrics, Harvard Medical School, Boston, MA (M.C.C.); and Division of Cardiovascular Surgery, Hospital of the University of Pennsylvania, Philadelphia (K.M.K.).
authors.forename: James S
authors.initials: JS
authors.lastname: Allan
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D003331:Coronary Vessels; D004195:Disease Models, Animal; D018450:Disease Progression; D004452:Echocardiography; D005500:Follow-Up Studies; D007075:Immunoglobulin M / Q000276:immunology*; D009203:Myocardial Infarction / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000276:immunology; D013552:Swine; D013556:Swine, Miniature; D020107:Troponin T / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D007075:Immunoglobulin M; D020107:Troponin T; D018995:Myosin Heavy Chains
keywords: immunology; inflammation; left ventricular function; myocardial infarction; troponin T