Image-guided therapies for myocardial repair: concepts and practical implementation

Abstract

Cell- and molecule-based therapeutic strategies to support wound healing and regeneration after myocardial infarction (MI) are under development. These emerging therapies aim at sustained preservation of ventricular function by enhancing tissue repair after myocardial ischaemia and reperfusion. Such therapies will benefit from guidance with regard to timing, regional targeting, suitable candidate selection, and effectiveness monitoring. Such guidance is effectively obtained by non-invasive tomographic imaging. Infarct size, tissue characteristics, muscle mass, and chamber geometry can be determined by magnetic resonance imaging and computed tomography. Radionuclide imaging can be used for the tracking of therapeutic agents and for the interrogation of molecular mechanisms such as inflammation, angiogenesis, and extracellular matrix activation. This review article portrays the hypothesis that an integrated approach with an early implementation of structural and molecular tomographic imaging in the development of novel therapies will provide a framework for achieving the goal of improved tissue repair after MI.

Keywords: Acute myocardial infarction; Computed tomography; Magnetic resonance; Molecular imaging; Myocardial regeneration; Wound healing.

Figure 1.

Emerging therapeutic targets in AMI (see text for details).

Figure 2.

Quantitative assessment of infarct and peri-infarct zones by delayed enhancement magnetic resonance imaging in a mini-pig model of MI. (A) Example of one myocardial short-axis slice followed over time until Day 90 post-MI. (B) The same myocardial slices with computer-generated mask depicting the core infarct (red) and peri-infarct zone (yellow). Generation of the masks has been validated against histology. The peri-infarct zone is most pronounced on Day 3 and diminishes thereafter. After Day 30, only little change in the extent of the peri-infarct zone is observed. Reprinted with permission from Schuleri et al.

Figure 3.

Characterization of tissue heterogeneity in the peri-infarct zone using delayed enhancement CT (A and B) and CMR (D and E) in a pig model. (C and F) Masson trichrome stain depicts a viable myocardium in red from non-viable tissue in blue. Scanning electron microscope images of the densely packed collagen fibres 6 months after MI (G) and viable myocytes (H) characterize the ultra-structure of the chronic infarct. (I) Transmission electron microscopy shows the clear delineating of the collagenous scar (white arrows) and viable tissue (asterisk). Reprinted with permission from Schuleri et al.

Figure 4.

Schematic display of molecular imaging targets in the healing myocardium. Cell death tracers bind to surface and intracellular structures. Radiotracers for receptors and cell–matrix interaction are available (see text). Recruited progenitor cells can be tracked by radionuclide labelling, using various tracers, or reporter gene technique (not shown). ACE, angiotensin-converting enzyme; AR, adrenoceptor; ATR, angiotensin receptor; HMPAO, hexamethylpropyleneamine oxime; MMP, matrix metalloproteinase; MR, muscarinic receptor. Adapted and reprinted with permission from Bengel.

Figure 5.

Examples of molecular PET imaging of post-infarct healing in a rat model of MI. (A) Specific accumulation of the alpha(v)beta(3) integrin-targeted tracer F-18 galactoRGD in the hypoperfused infarct area, but not in a sham model without perfusion defect. Note the additional presence of integrin expression in the chest wall in both settings. (B) Specific accumulation of the angiotensin II type 1 receptor ligand C-11 KR31173 at 1 week after ischaemia–reperfusion (top), which is abolished by blocking with a high dose of non-labelled receptor ligand (bottom). Reprinted with permission from Higuchi et al.^,

Figure 6.

Integrated imaging of post-infarct inflammation by hybrid PET–CT. (A) Different CT-delayed enhancement patterns after MI in a pig model. (B) Integration of CT with PET-derived myocardial perfusion (N-13 ammonia, NH₃) and glucose utilization (F-18 deoxyglucose, FDG) under fasting conditions. (C) Quantitative confirmation that glucose utilization in the infarct region is increased in the acute, but not in the chronic phase. (D) Histological confirmation that increased glucose utilization in the acute infarct region is at least in part due to massive inflammation (indicated by blue staining of inflammatory cells). Please note that viable myocytes, despite fasting, may also show increased FDG uptake, as seen in the remote myocardium. Only the integration of FDG signal and CT (which localizes FDG uptake to transmural scar) can be used to identify post-infarct inflammation. Adapted and reprinted with permission from Lautamaki et al.