Dara L. Kraitchman

In Vivo Magnetic Resonance Imaging of Mesenchymal Stem Cells in Myocardial Infarction

Background—We investigated the potential of magnetic resonance imaging (MRI) to track magnetically labeled mesenchymal stem cells (MR-MSCs) in a swine myocardial infarction (MI) model. Methods and Results—Adult farm pigs (n=5) were subjected to closed-chest experimental MI. MR-MSCs (2.8 to 16×107 cells) were injected intramyocardially under x-ray fluoroscopy. MRIs were obtained on a 1.5T MR scanner to demonstrate the location of the MR-MSCs and were correlated with histology. Contrast-enhanced MRI demonstrated successful injection in the infarct and serial MSC tracking was demonstrated in two animals. Conclusion—MRI tracking of MSCs is feasible and represents a preferred method for studying the engraftment of MSCs in MI.

Dynamic Imaging of Allogeneic Mesenchymal Stem Cells Trafficking to Myocardial Infarction

Background—Recent results from animal studies suggest that stem cells may be able to home to sites of myocardial injury to assist in tissue regeneration. However, the histological interpretation of postmortem tissue, on which many of these studies are based, has recently been widely debated. Methods and Results—With the use of the high sensitivity of a combined single-photon emission CT (SPECT)/CT scanner, the in vivo trafficking of allogeneic mesenchymal stem cells (MSCs) colabeled with a radiotracer and MR contrast agent to acute myocardial infarction was dynamically determined. Redistribution of the labeled MSCs after intravenous injection from initial localization in the lungs to nontarget organs such as the liver, kidney, and spleen was observed within 24 to 48 hours after injection. Focal and diffuse uptake of MSCs in the infarcted myocardium was already visible in SPECT/CT images in the first 24 hours after injection and persisted until 7 days after injection and was validated by tissue counts of radioactivity. In contrast, MRI was unable to demonstrate targeted cardiac localization of MSCs in part because of the lower sensitivity of MRI. Conclusions—Noninvasive radionuclide imaging is well suited to dynamically track the biodistribution and trafficking of mesenchymal stem cells to both target and nontarget organs.

Tracking and finite element analysis of stripe deformation in magnetic resonance tagging

Magnetic resonance tissue tagging allows noninvasive in vivo measurement of soft tissue deformation. Planes of magnetic saturation are created, orthogonal to the imaging plane, which form dark lines (stripes) in the image. The authors describe a method for tracking stripe motion in the image plane, and show how this information can be incorporated into a finite element model of the underlying deformation. Human heart data were acquired from several imaging planes in different orientations and were combined using a deformable model of the left ventricle wall. Each tracked stripe point provided information on displacement orthogonal to the original tagging plane, i.e., a one-dimensional (1-D) constraint on the motion. Three-dimensional (3-D) motion and deformation was then reconstructed by fitting the model to the data constraints by linear least squares. The average root mean squared (rms) error between tracked stripe points and predicted model locations was 0.47 mm (n=3,100 points). In order to validate this method and quantify the errors involved, the authors applied it to images of a silicone gel phantom subjected to a known, well-controlled, 3-D deformation. The finite element strains obtained were compared to an analytic model of the deformation known to be accurate in the central axial plane of the phantom. The average rms errors were 6% in both the reconstructed shear strains and 16% in the reconstructed radial normal strain.

Positive contrast visualization of iron oxide‐labeled stem cells using inversion‐recovery with ON‐resonant water suppression (IRON)

In proton magnetic resonance imaging (MRI) metallic substances lead to magnetic field distortions that often result in signal voids in the adjacent anatomic structures. Thus, metallic objects and superparamagnetic iron oxide (SPIO)‐labeled cells appear as hypointense artifacts that obscure the underlying anatomy. The ability to illuminate these structures with positive contrast would enhance noninvasive MR tracking of cellular therapeutics. Therefore, an MRI methodology that selectively highlights areas of metallic objects has been developed. Inversion‐recovery with ON‐resonant water suppression (IRON) employs inversion of the magnetization in conjunction with a spectrally‐selective on‐resonant saturation prepulse. If imaging is performed after these prepulses, positive signal is obtained from off‐resonant protons in close proximity to the metallic objects. The first successful use of IRON to produce positive contrast in areas of metallic spheres and SPIO‐labeled stem cells in vitro and in vivo is presented. Magn Reson Med 58:1072–1077, 2007.

111In oxine labelled mesenchymal stem cell SPECT after intravenous administration in myocardial infarction

Mesenchymal stem cells (MSCs) have shown therapeutic potential if successfully delivered to the intended site of myocardial infarction. The purpose of this pilot study was to test the feasibility of 111In oxine labelling of MSCs and single photon emission computed tomography (SPECT) imaging after intravenous administration in a porcine model of myocardial infarction. Adult farm pigs (n = 2) were subjected to closed chest experimental myocardial infarction. 111In oxine labelled MSCs (1×107 to 2×107 cells) were infused intravenously, and SPECT imaging was performed initially and on days 1, 2, 7 and 14. High quality SPECT images were obtained through 2 weeks of imaging. High initial MSC localization occurred in the lungs and slow progressive accumulation occurred in the liver, spleen and bone marrow. Renal activity was mild and persistent throughout imaging. No appreciable accumulation occurred in the myocardium. It is concluded that 111In oxine radiolabelling of MSCs is feasible, and in vivo imaging with SPECT provides a non-invasive method for sequentially monitoring cell trafficking with good spatial resolution. Because intravenous administration of MSCs results in significant lung activity that obscures the assessment of myocardial cell trafficking, alternative routes of administration should be investigated for this application.

Magnetic resonance–guided, real-time targeted delivery and imaging of magnetocapsules immunoprotecting pancreatic islet cells

In type I diabetes mellitus, islet transplantation provides a moment-to-moment fine regulation of insulin. Success rates vary widely, however, necessitating suitable methods to monitor islet delivery, engraftment and survival. Here magnetic resonance–trackable magnetocapsules have been used simultaneously to immunoprotect pancreatic β-cells and to monitor, non-invasively in real-time, hepatic delivery and engraftment by magnetic resonance imaging (MRI). Magnetocapsules were detected as single capsules with an altered magnetic resonance appearance on capsule rupture. Magnetocapsules were functional in vivo because mouse β-cells restored normal glycemia in streptozotocin-induced diabetic mice and human islets induced sustained C-peptide levels in swine. In this large-animal model, magnetocapsules could be precisely targeted for infusion by using magnetic resonance fluoroscopy, whereas MRI facilitated monitoring of liver engraftment over time. These findings are directly applicable to ongoing improvements in islet cell transplantation for human diabetes, particularly because our magnetocapsules comprise clinically applicable materials.

Monitoring Cell Therapy Using Iron Oxide MR Contrast Agents

Given the remarkable progress that has recently been obtained in animal studies, the clinical use of stem and progenitor cells to correct or replace defective cell populations may soon become a reality. In order to develop effective cell therapies, the location and distribution of these cells must be determined in a non-invasive manner. Magnetic resonance (MR) tracking of magnetically labeled cells following transplantation or transfusion may fulfill this requirement. Indeed, a series of recent studies indicate that MRI cell tracking has great potential for further evaluation and optimization of cell therapy. Due to its biocompatibility and strong effects on T2(*) relaxation, iron oxide nanoparticles appear to be the contrast agent of choice, and several methods now exist to shuttle sufficient amount of these compounds into cells. Most of the tracking work has been carried out in disease models of the central nervous system, but, recently, the infarcted heart has also received attention. With its excellent spatial resolution and the ability to track labeled cells over prolonged periods of time, MR monitoring of cell therapy is likely to become an important technique in the foreseeable future.

Multimodality Cardiovascular Molecular Imaging, Part II

Molecular imaging has the potential to profoundly impact preclinical research and future clinical cardiovascular care. In Part I of this 2-part consensus article on multimodality cardiovascular molecular imaging, the imaging methodology, evolving imaging technology, and development of novel targeted molecular probes relevant to the developing field of cardiovascular molecular imaging were reviewed.1 Part II of this consensus article will review the targeted imaging probes available for the identification and evaluation of critical pathophysiological processes in the cardiovascular system. These include novel imaging strategies for the evaluation of inflammation, thrombosis, apoptosis, necrosis, vascular remodeling, and angiogenesis. The current article will also review the role of targeted imaging of a number of cardiovascular diseases, including atherosclerosis, ischemic injury, postinfarction remodeling, and heart failure, as well as the emerging fields of regenerative, genetic, and cell-based therapies. Special emphasis is placed on multimodal imaging, as these hybrid techniques promise to advance the field by combining approaches with complementary strengths and off-setting limitations.2,3 Although some applications of molecular imaging are well established, other clinical applications are under development and still emerging, such as early detection of atherosclerosis or unstable plaque.4 The goals of molecular imaging are to refine risk assessment, facilitate the early diagnosis of disease before the occurrence of debilitating events, aid in the development of personalized therapeutic regimens and to monitor the efficacy of complex therapies. However, to translate the evolving targeted imaging probes, technologies, and applications into clinical care, the imaging community will need to overcome several hurdles. Therefore, the current review will also discuss the opportunities and challenges associated with the implementation and advancement of targeted molecular imaging in clinical practice, and the realization of image-directed personalized medicine.

Noninvasive Detection of Macrophage-rich Atherosclerotic Plaque in Hyperlipidemic Rabbits using ‘Positive Contrast’ Magnetic Resonance Imaging

OBJECTIVES This study was designed to identify macrophage-rich atherosclerotic plaque noninvasively by imaging the tissue uptake of long-circulating superparamagnetic nanoparticles with a positive contrast off-resonance imaging sequence (inversion recovery with ON-resonant water suppression [IRON]). BACKGROUND The sudden rupture of macrophage-rich atherosclerotic plaques can trigger the formation of an occlusive thrombus in coronary vessels, resulting in acute myocardial infarction. Therefore, a noninvasive technique that can identify macrophage-rich plaques and thereby assist with risk stratification of patients with atherosclerosis would be of great potential clinical utility. METHODS Experiments were conducted on a clinical 3-T magnetic resonance imaging (MRI) scanner in 7 heritable hyperlipidemic and 4 control rabbits. Monocrystalline iron-oxide nanoparticles (MION)-47 were administrated intravenously (2 doses of 250 mumol Fe/kg), and animals underwent serial IRON-MRI before injection of the nanoparticles and serially after 1, 3, and 6 days. RESULTS After administration of MION-47, a striking signal enhancement was found in areas of plaque only in hyperlipidemic rabbits. The magnitude of enhancement on magnetic resonance images had a high correlation with the number of macrophages determined by histology (p < 0.001) and allowed for the detection of macrophage-rich plaque with high accuracy (area under the curve: 0.92, SE: 0.04, 95% confidence interval: 0.84 to 0.96, p < 0.001). No significant signal enhancement was measured in remote areas without plaque by histology and in control rabbits without atherosclerosis. CONCLUSIONS Using IRON-MRI in conjunction with superparamagnetic nanoparticles is a promising approach for the noninvasive evaluation of macrophage-rich, vulnerable plaques.

Quantitative Ischemia Detection During Cardiac Magnetic Resonance Stress Testing by Use of FastHARP

Background—Because ECG alterations caused by ischemia cannot be reliably detected in the high-field MRI environment, detection of wall motion abnormalities is often used to ensure patient safety during stress testing. However, an experienced observer is needed to detect these abnormalities. In this study, we investigate the use of fast harmonic phase (FastHARP) MRI for the quantitative, operator-independent detection of the onset of ischemia during acute coronary occlusion. Methods and Results—Eight mongrel dogs underwent an acute 2-minute closed-chest coronary artery occlusion while continuous FastHARP images were acquired. Full regional wall strain was determined every other heartbeat in a single short-axis imaging slice. After 5 minutes of reperfusion, a second 2-minute ischemic episode was induced during the acquisition of conventional cine wall-motion images. The time at which ECG alterations were observed during the first ischemic period was recorded. The time from occlusion to the detection of ischemia, based on a consensus of 2 blinded observers, was determined for MRI. No significant ischemia was present in 2 animals. In the remaining animals, the onset of ischemia was detected significantly earlier by FastHARP than by cine MRI (9.5±5 versus 33±14 seconds, P <0.01). HARP ischemia detection preceded ECG changes, on average, by 54 seconds. Conclusions—The rapid acquisition and detection of induced ischemia with FastHARP MRI shows promise as a nonsubjective method to diagnose significant coronary lesions during MR stress testing.