Wesley D. Gilson

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.

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.

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.

Simultaneous Evaluation of Infarct Size and Cardiac Function in Intact Mice by Contrast-Enhanced Cardiac Magnetic Resonance Imaging Reveals Contractile Dysfunction in Noninfarcted Regions Early After Myocardial Infarction

Background—The objective of this study was to noninvasively determine the effects of reperfused myocardial infarction (MI) on regional and global left-ventricular (LV) function 24 hours after MI in intact mice with contrast-enhanced cardiac MRI and a single, gradient-echo pulse sequence. Methods and Results—Twenty-three mice received baseline MRI scans followed by either 60 minutes of coronary occlusion (MI group, n=15) or thoracotomy without occlusion (sham group, n=8). Gadolinium-DTPA–enhanced magnetic resonance (MR) images were acquired 24 hours after surgery. Hearts were then excised for conventional infarct size determination via 2,3,5-triphenyl tetrazolium chloride (TTC) staining. In addition to infarct size, analysis of the MR images yielded left ventricular (LV) mass, LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV), LV ejection fraction (LVEF), cardiac output, and percent LV wall thickening (%WTh). Twenty-four hours after surgery, infarct size was 28.1±1.8% of LV mass by MRI and 27.5±1.7% by TTC (P =NS). Bland-Altman analysis revealed close agreement between the results obtained by the 2 methods. MI had little effect on LVEDV but caused a 98% increase in LVESV (from 11.3 to 22.4 &mgr;L, P <0.05), which resulted in a significant reduction in LVEF (from 70% to 37%, P <0.05). Compared with LV regional function at baseline, %WTh 24 hours after MI was significantly depressed, not only in infarcted myocardium but also in regions remote from the infarct zone. In contrast, sham-operated mice showed a small but significant increase in %WTh 24 hours after surgery (P <0.05). Conclusions—MRI can accurately assess both infarct size and cardiac function in intact mice early after large, reperfused MI, revealing the existence of contractile dysfunction in noninfarcted regions of the heart.

MR tagging early after myocardial infarction in mice demonstrates contractile dysfunction in adjacent and remote regions

The purpose of this study was to use MR myocardial tagging to assess regional cardiac function after myocardial infarction (MI) in mice. Eight mice were imaged before and 1 day after MI. MRI included cine imaging, myocardial tagging, and contrast‐enhanced imaging. Regional percent circumferential shortening (%CS) was measured from the tagged images, and the region of hyperenhancement on the contrast‐enhanced images was used to determine the infarcted, adjacent, and remote zones. Ejection fraction (EF) fell from 59% ± 6% at baseline to 32% ± 6% after MI (P < 0.01). At baseline, %CS was 14.5% ± 3.4%. After MI, %CS was 0.7% ± 4.4% in the infarcted zone, 7.4% ± 4.4% in the adjacent zone, and 11.8% ± 4.2% in the remote zone. %CS was statistically different for all comparisons between the infarcted, adjacent, remote, and baseline groups (P < 0.01). MR tagging can detect regional differences in myocardial function post‐MI in mice. Magn Reson Med 48:399–403, 2002.

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.

Serial MRI evaluation of cardiac structure and function in mice after reperfused myocardial infarction

This study evaluated the utility of cardiac MRI for assessing the impact of myocardial infarction (MI) on cardiac structure and function in mice following reperfused 1‐ or 2‐hr occlusions of the left anterior descending coronary artery (LAD). When assessed 1 day after MI, the left ventricular ejection fraction (LVEF) had declined by more than half, and remained depressed for the duration of the study. Furthermore, MI initiated dramatic increases in both LV end‐systolic volume (LVESV) and end‐diastolic volume (LVEDV), with a greater than threefold increase in LVESV and a twofold increase in LVEDV by 4 weeks post‐MI. Transmural LV wall thickening (WTh) analysis revealed that noninfarcted myocardium in the remote septal region exhibited an early deficit in contractile function after MI that transiently resolved by day 7, only to be followed by a late phase of dysfunction that became fully manifest by day 28 post‐MI. In conclusion, MRI allows the serial assessment of cardiac structure and function after MI in mice, with a resolution adequate to document both regional and temporal changes. The application of these imaging techniques in transgenic and knock‐out mice will greatly expedite research aimed at defining the functional roles of individual genes in the pathophysiology of LV remodeling (LVR) after reperfused MI. Magn Reson Med 47:1158–1168, 2002.

Complementary displacement‐encoded MRI for contrast‐enhanced infarct detection and quantification of myocardial function in mice

MRI is emerging as an important modality for assessing myocardial function in transgenic and knockout mouse models of cardiovascular disease, including myocardial infarction (MI). Displacement encoding with stimulated echoes (DENSE) measures myocardial motion at high spatial resolution using phase‐reconstructed images. The current DENSE technique uses inversion recovery (IR) to suppress T1‐relaxation artifacts; however, IR is ill‐suited for contrast‐enhanced infarct imaging in the heart, where multiple T1 values are observed. We have developed a modified DENSE method employing complementary acquisitions for T1‐independent artifact suppression. With this technique, displacement and strain are measured in phase‐reconstructed images, and contrast‐enhanced regions of infarction are depicted in perfectly coregistered magnitude‐reconstructed images. The displacement measurements and T1‐weighted image contrast were validated with the use of a rotating phantom. Modified DENSE was performed in mice (N = 9) before and after MI. Circumferential (Ecc) and radial (Err) strain were measured, and contrast‐enhanced infarcted myocardium was detected by DENSE. At baseline, Ecc was −0.16 ± 0.01 and Err was 0.39 ± 0.07. After MI, Ecc was 0.04 ± 0.02 and Err was 0.03 ± 0.04 in infarcted regions, whereas Ecc was −0.12 ± 0.02 and Err was 0.38 ± 0.09 in noninfarcted regions. In vivo Ecc as determined by DENSE correlated well with Ecc obtained by conventional tag analysis (R = 0.90). Magn Reson Med 51:744–752, 2004.

Real-time imaging of regional myocardial function using fast-SENC.

A technique for fast imaging of regional myocardial function using a spiral acquisition in combination with strain‐encoded (SENC) magnetic resonance imaging (MRI) is presented in this paper. This technique, which is termed fast‐SENC, enables scan durations as short as a single heartbeat. A reduced field of view (FOV) without foldover artifacts was achieved by localized SENC, which selectively excited the region around the heart. The two images required for SENC imaging (low‐ and high‐tuning) were acquired in an interleaved fashion throughout the cardiac cycle to further shorten the scan time. Regional circumferential contraction and longitudinal shortening of both the left ventricle (LV) and right ventricle (RV) were examined in long‐ and short‐axis views, respectively. The in vivo results obtained from five human subjects and five infarcted dogs are presented. The results of the fast‐SENC technique in a single heartbeat acquisition were comparable to those obtained by conventional SENC in a long acquisition time. Therefore, fast‐SENC may prove useful for imaging during stress or arrhythmia. Magn Reson Med, 2006.

Stem cell therapy: MRI guidance and monitoring

With the recent advances in magnetic resonance (MR) labeling of cellular therapeutics, it is natural that interventional MRI techniques for targeting would be developed. This review provides an overview of the current methods of stem cell labeling and the challenges that are created with respect to interventional MRI administration. In particular, stem cell therapies will require specialized, MR‐compatible devices as well as integration of graphical user interfaces with pulse sequences designed for interactive, real‐time delivery in many organs. Specific applications that are being developed will be reviewed as well as strategies for future translation to the clinical realm. J. Magn. Reson. Imaging 2008;27:299–310.