title: Transglutaminase activity in acute infarcts predicts healing outcome and left ventricular remodelling: implications for FXIII therapy and antithrombin use in myocardial infarction.
abstract: OBJECTIVE
  The transglutaminase factor XIII (FXIII) emerges as a key enzyme in healing after myocardial infarction (MI). Here we assess the impact of transglutaminase-modulating therapies on healing and evolution of heart failure using a novel, non-invasive molecular imaging technique.
  
  
  RESULTS
  Immunoblotting revealed lower FXIII levels in the myocardium of nine patients with infarct rupture when compared to MI patients without rupture (P < 0.0045). In a murine model of MI, we assessed healing while modulating local FXIII activity. Infarct tissue activity was monitored with molecular in vivo single photon emission computed tomography-computed tomography (SPECT-CT) imaging, and activity was found to be increased by 80% in FXIII-treated mice (400 IU FXIII/kg iv.), and decreased by 65% in dalteparin (DP)-treated mice (600 IU/kg DP sc., P < 0.05). DP-treated mice exhibited increased mortality due to infarct rupture (64% by day 7, P < 0.018). Serial Magnetic Resonance Imaging (MRI) showed that left ventricular dilation post-MI was attenuated by FXIII treatment when compared to saline control-treated mice with MI (P = 0.04). Quantitative histological and reverse transcription-polymerase chain reaction analyses revealed that FXIII treatment induced a faster resolution of the neutrophil response, enhanced macrophage recruitment, increased collagen content and augmented angiogenesis in the healing infarct (P < 0.05 vs. control-treated mice with MI).
  
  
  CONCLUSIONS
  FXIII tissue levels are decreased in patients with insufficient healing. Therapeutic strategies that modulate FXIII activity impact murine myocardial healing. Molecular imaging of FXIII activity predicts prognosis in mice with experimental MI.
authors.affiliation: Center for Molecular Imaging Research, Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Room 5406, Charlestown, MA 02129, USA. mnahrendorf@mgh.harvard.edu
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.forename: Elena
authors.initials: E
authors.lastname: Aikawa
authors.forename: Jose-Luiz
authors.initials: JL
authors.lastname: Figueiredo
authors.forename: Lars
authors.initials: L
authors.lastname: Stangenberg
authors.forename: Susanne W
authors.initials: SW
authors.lastname: van den Borne
authors.forename: W Matthijs
authors.initials: WM
authors.lastname: Blankesteijn
authors.forename: David E
authors.initials: DE
authors.lastname: Sosnovik
authors.forename: Farouc A
authors.initials: FA
authors.lastname: Jaffer
authors.forename: Ching-Hsuan
authors.initials: CH
authors.lastname: Tung
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D003094:Collagen / Q000096:biosynthesis; D017985:Dalteparin / Q000627:therapeutic use; D005176:Factor XIII / Q000627:therapeutic use*; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006342:Heart Rupture, Post-Infarction / Q000517:prevention & control; D006801:Humans; D018810:Magnetic Resonance Angiography / Q000379:methods; D051379:Mice; D009203:Myocardial Infarction / Q000503:physiopathology / Q000517:prevention & control*; D013318:Stroke Volume / Q000502:physiology; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D016896:Treatment Outcome; D016277:Ventricular Function, Left / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D000925:Anticoagulants; D005343:Fibrinolytic Agents; D003094:Collagen; D005176:Factor XIII; D017985:Dalteparin