The problem. Myocardial infarction causes heart failure in many patients. In the previous funding period, we found that infarct inflammation and the efficiency of infarct healing predicts heart failure, generating interest in targeting these processes therapeutically. Initially, inflammatory monocytes and classical M1 macrophages remove debris from the wound, but their activity must resolve in a timely fashion to allow extracellular matrix regeneration. If resolution of inflammation is compromised, the emerging scar is weak and expands, leading to left ventricular dilation. Supported by this grant, we found that FMT/CT imaging reports on key wound healing components such as inflammation and matrix regeneration. FMT/CT facilitated our understanding of basic cardiovascular biology and enabled discoveries such as the splenic monocyte reservoir (Science 2009) and activation of the hematopoietic system after MI (Nature 2012). We identified and validated clusters of imaging biomarkers reflecting diverse biological processes in the wound. However, physical limitations preclude the use of optical imaging to assess infarct healing in humans. To translate our basic science discoveries into the clinic, the goal of this renewal application is to develop a clinically viable PET/MRI approach to follow infarct healing, to quantify risk for post-MI heart failure, and to monitor efficacy of new heart failure therapeutics. Innovation. Based on work in the previous funding period, we selected 2 targets that reflect contrasting aspects of healing: transglutaminase activity (to be imaged with PET) and macrophages (to be imaged with MRI). We hypothesize that hybrid PET/MRI, covering regenerative matrix repair and destructive inflammatory tissue removal, i.e. the 'yin and yang' of healing, will predict post-MI heart failure A fluorine-18 labeled substrate peptide (dubbed 18F- FXIII) will target transglutaminase, an enzyme critically involved in the final steps of extracellular matrix crosslinking. Genetic and acquired lack of this enzyme causes infarct rupture due to insufficient matrix regeneration. We will optimize target affinity and biodistribution of an existing first-generation agent by explorin a rationally designed mini-library. Agent specificity will be validated in mice that are genetically deficient for transglutaminase. The best PET agent will advance into hybrid PET/MRI, where iron oxide nanoparticles simultaneously evaluate infarct macrophages, as validated by us for FMT/CT and MRI in the previous funding period. We will test the utility and predictive value of PET/MRI in a setting of impaired wound healing in atherosclerotic ApoE-/- mice with an inflammation-resolution-deficit phenotype. We will image mice receiving novel candidate therapeutics that improve infarct healing by transglutaminase supplementation and immunoediting. A PET/MRI trial in swine with acute MI will test the translational potential in larg animals. Impact. Our ultimate goals are i) to develop new therapeutics to combat post-MI heart failure, ii) to establish an imaging strategy that identifies patients with increased risk of heart failure after MI, and a companion imaging tool for therapeutic trials.

Public Health Relevance

The goals of this application are to develop new therapeutics to combat post-MI heart failure, to establish an imaging strategy that identifies patients with increased risk of heart failure after MI, and a companion imaging tool for therapeutic trials.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HL096576-07
Application #
9197680
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Danthi, Narasimhan
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Dutta, Partha; Hoyer, Friedrich Felix; Sun, Yuan et al. (2016) E-Selectin Inhibition Mitigates Splenic HSC Activation and Myelopoiesis in Hypercholesterolemic Mice With Myocardial Infarction. Arterioscler Thromb Vasc Biol 36:1802-8
Swirski, Filip K; Nahrendorf, Matthias (2016) Bone Marrow Takes Center Stage in Cardiovascular Disease. Circ Res 119:701-3
Hulsmans, Maarten; Sam, Flora; Nahrendorf, Matthias (2016) Monocyte and macrophage contributions to cardiac remodeling. J Mol Cell Cardiol 93:149-55
Sager, Hendrik B; Dutta, Partha; Dahlman, James E et al. (2016) RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction. Sci Transl Med 8:342ra80
Rischpler, Christoph; Dirschinger, Ralf J; Nekolla, Stephan G et al. (2016) Prospective Evaluation of 18F-Fluorodeoxyglucose Uptake in Postischemic Myocardium by Simultaneous Positron Emission Tomography/Magnetic Resonance Imaging as a Prognostic Marker of Functional Outcome. Circ Cardiovasc Imaging 9:e004316
Nahrendorf, Matthias; Swirski, Filip K (2016) Abandoning M1/M2 for a Network Model of Macrophage Function. Circ Res 119:414-7
Nahrendorf, Matthias; Swirski, Filip K (2015) PET Imaging of Leukocytes in Patients With Acute Myocardial Infarction. JACC Cardiovasc Imaging 8:1427-9
Dutta, Partha; Sager, Hendrik B; Stengel, Kristy R et al. (2015) Myocardial Infarction Activates CCR2(+) Hematopoietic Stem and Progenitor Cells. Cell Stem Cell 16:477-87
Nahrendorf, Matthias; Frantz, Stefan; Swirski, Filip K et al. (2015) Imaging systemic inflammatory networks in ischemic heart disease. J Am Coll Cardiol 65:1583-91
Sager, Hendrik B; Heidt, Timo; Hulsmans, Maarten et al. (2015) Targeting Interleukin-1β Reduces Leukocyte Production After Acute Myocardial Infarction. Circulation 132:1880-90

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