Venkatesh K. Raman

Serial Cardiac Magnetic Resonance Imaging of Injected Mesenchymal Stem Cells

Background—Delivery and tracking of endomyocardial stem cells are limited by the inability to image transplanted cells noninvasively in the beating heart. We hypothesized that mesenchymal stem cells (MSCs) could be labeled with a iron fluorophore particle (IFP) to provide MRI contrast in vivo to assess immediate and long-term localization. Methods and Results—MSCs were isolated from swine. Short-term incubation of MSCs with IFP resulted in dose-dependent and efficient labeling. Labeled cells remained viable for multiple passages and retained in vitro proliferation and differentiation capacity. Labeled MSCs (104 to 106 cells/150 &mgr;L) were injected percutaneously into normal and freshly infarcted myocardium in swine. One, 3, and 1 animals underwent serial cardiac MRI (1.5T) for 4, 8, and 21 days, respectively. MRI contrast properties were measured both in vivo and in vitro for cells embedded in agar. Injection sites containing as few as 105 MSCs could be detected and contained intact IFP-bearing MSCs on histology. Conclusions—IFP labeling of MSCs imparts useful MRI contrast, enabling ready detection in the beating heart on a conventional cardiac MR scanner after transplantation into normal and infarcted myocardium. The dual-labeled MSCs can be identified at locations corresponding to injection sites, both ex vivo using fluorescence microscopy and in vivo using susceptibility contrast on MRI. This technology may permit effective in vivo study of stem cell retention, engraftment, and migration.

Magnetic Resonance Fluoroscopy Allows Targeted Delivery of Mesenchymal Stem Cells to Infarct Borders in Swine

Background—The local environment of delivered mesenchymal stem cells (MSCs) may affect their ultimate phenotype. MR fluoroscopy has the potential to guide intramyocardial MSC injection to desirable targets, such as the border between infarcted and normal tissue. We tested the ability to (1) identify infarcts, (2) navigate injection catheters to preselected targets, (3) inject safely even into fresh infarcts, and (4) confirm injection success immediately. Methods and Results—A 1.5-T MRI scanner was customized for interventional use, with rapid imaging, independent color highlighting of catheter channels, multiple-slice 3D rendering, catheter-only viewing mode, and infarct-enhanced imaging. MRI receiver coils were incorporated into guiding catheters and injection needles. These devices were tested for heating and used for targeted MSC delivery. In infarcted pigs, myocardium was targeted by MR fluoroscopy. Infarct-enhanced imaging included both saturation preparation MRI after intravenous gadolinium and wall motion. Porcine MSCs were MRI-labeled with iron-fluorescent particles. Catheter navigation and multiple cell injections were performed entirely with MR fluoroscopy at 8 frames/s with 1.7×3.3×8-mm voxels. Infarct-enhanced MR fluoroscopy permitted excellent delineation of infarct borders. All injections were safely and successfully delivered to their preselected targets, including infarct borders. Iron-fluorescent particle–labeled MSCs were readily visible on delivery in vivo and post mortem. Conclusions—Precise targeted delivery of potentially regenerative cellular treatments to recent myocardial infarction borders is feasible with an MR catheter delivery system. MR fluoroscopy permits visualization of catheter navigation, myocardial function, infarct borders, and labeled cells after injection.

Catheter-based endomyocardial injection with real-time magnetic resonance imaging

Background—We tested the feasibility of targeted left ventricular (LV) mural injection using real-time MRI (rtMRI). Methods and Results—A 1.5T MRI scanner was customized with a fast reconstruction engine, transfemoral guiding catheter–receiver coil (GCC), MRI-compatible needle, and tableside consoles. Commercial real-time imaging software was customized to facilitate catheter navigation and visualization of injections at 4 completely refreshed frames per second. The aorta was traversed and the left ventricular cavity was entered under direct rtMRI guidance. Pigs underwent multiple injections with dilute gadolinium-DTPA. All myocardial segments were readily accessed. The active GCC and the passive Stiletto needle injector were readily visualized. More than 50 endomyocardial injections were performed with the aid of rtMRI; 81% were successful with this first-generation prototype. Conclusion—Percutaneous endomyocardial drug delivery is feasible with the aid of rtMRI, which permits precise 3-dimensional localization of injection within the LV wall.

Real-Time Magnetic Resonance Imaging–Guided Stenting of Aortic Coarctation With Commercially Available Catheter Devices in Swine

Background—Real-time MR imaging (rtMRI) is now technically capable of guiding catheter-based cardiovascular interventions. Compared with x-ray, rtMRI offers superior tissue imaging in any orientation without ionizing radiation. Translation to clinical trials has awaited the availability of clinical-grade catheter devices that are both MRI visible and safe. We report a preclinical safety and feasibility study of rtMRI-guided stenting in a porcine model of aortic coarctation using only commercially available catheter devices. Method and Results—Coarctation stenting was performed wholly under rtMRI guidance in 13 swine. rtMRI permitted procedure planning, device tracking, and accurate stent deployment. “Active” guidewires, incorporating MRI antennas, improved device visualization compared with unmodified “passive” nitinol guidewires and shortened procedure time (26±11 versus 106±42 minutes; P=0.008). Follow-up catheterization and necropsy showed accurate stent deployment, durable gradient reduction, and appropriate neointimal formation. MRI immediately identified aortic rupture when oversized devices were tested. Conclusions—This experience demonstrates preclinical safety and feasibility of rtMRI-guided aortic coarctation stenting using commercially available catheter devices. Patients may benefit from rtMRI in the future because of combined device and tissue imaging, freedom from ionizing radiation, and the ability to identify serious complications promptly.

Real-Time Magnetic Resonance Imaging–Guided Endovascular Recanalization of Chronic Total Arterial Occlusion in a Swine Model

Background— Endovascular recanalization (guidewire traversal) of peripheral artery chronic total occlusion (CTO) can be challenging. X-ray angiography resolves CTO poorly. Virtually “blind” device advancement during x-ray–guided interventions can lead to procedure failure, perforation, and hemorrhage. Alternatively, MRI may delineate the artery within the occluded segment to enhance procedural safety and success. We hypothesized that real-time MRI (rtMRI)–guided CTO recanalization can be accomplished in an animal model. Methods and Results— Carotid artery CTO was created by balloon injury in 19 lipid-overfed swine. After 6 to 8 weeks, 2 underwent direct necropsy analysis for histology, 3 underwent primary x-ray–guided CTO recanalization attempts, and the remaining 14 underwent rtMRI-guided recanalization attempts in a 1.5-T interventional MRI system. Real-time MRI intervention used custom CTO catheters and guidewires that incorporated MRI receiver antennae to enhance device visibility. The mean length of the occluded segments was 13.3±1.6 cm. The rtMRI-guided CTO recanalization was successful in 11 of 14 swine and in only 1 of 3 swine with the use of x-ray alone. After unsuccessful rtMRI (n=3), x-ray–guided attempts were also unsuccessful. Conclusions— Recanalization of long CTO is entirely feasible with the use of rtMRI guidance. Low-profile clinical-grade devices will be required to translate this experience to humans.

Invasive Human Magnetic Resonance Imaging: Feasibility During Revascularization in a Combined XMR Suite

We tested the feasibility and safety of invasive magnetic resonance imaging (MRI) during peripheral angioplasty. Real‐time MRI can image soft tissue and may potentially guide therapeutic procedures without ionizing radiation or nephrotoxic contrast. MRI‐guided diagnostic catheterization has been described recently, but safe and conspicuous catheter devices are not widely available. An active guidewire, which serves as an MRI receiver antenna, might be useful to guide catheterization or even to image atheroma. We describe a combined interventional suite offering both X‐ray fluoroscopy and real‐time MRI. We used a 0.030″ active guidewire receiver coil for invasive MRI after X‐ray lesion traversal in patients undergoing percutaneous iliofemoral artery revascularization. Intravascular MRI was compared with noninvasive MRI, X‐ray angiography, and intravascular ultrasound (IVUS). Seven eligible patients consented to participate, but three were excluded because of lengthy revascularization procedures. Four remaining patients safely underwent combined X‐ray fluoroscopy and real‐time magnetic resonance imaging (XMR) transport, continuous monitoring, and all imaging modalities. There was no device dislodgment, contamination or evidence of heating. The intravascular MRI coil was well visualized except at the tip, but did not provide superior mural imaging compared with IVUS. Therefore, because an adequate safety and workflow experience was obtained, enrollment was terminated after only four subjects. Invasive MRI is feasible and apparently safe during peripheral angioplasty. Patients can safely be transported and monitored in an XMR interventional suite. An active quarter‐wavelength guidewire coil does not provide superior imaging compared with IVUS, but provides satisfactory guidewire visualization. These tools may prove useful for advanced therapeutic procedures in the future. Catheter Cardiovasc Interv 2005;64:265–274. Published 2005 Wiley‐Liss, Inc.

Technology Preview: X-Ray Fused With Magnetic Resonance During Invasive Cardiovascular Procedures

We have developed and validated a system for real‐time X‐ray fused with magnetic resonance imaging, MRI (XFM), to guide catheter procedures with high spatial precision. Our implementation overlays roadmaps—MRI‐derived soft‐tissue features of interest—onto conventional X‐ray fluoroscopy. We report our initial clinical experience applying XFM, using external fiducial markers, electrocardiogram (ECG)‐ gating, and automated real‐time correction for gantry and table movement.

Interventional cardiovascular procedures guided by real-time MR imaging: An interactive interface using multiple slices, adaptive projection modes and live 3D renderings

To develop and test a novel interactive real‐time MRI environment that facilitates image‐guided cardiovascular interventions.

Measurement of Skeletal Muscle Perfusion During Postischemic Reactive Hyperemia Using Contrast-Enhanced MRI With a Step-Input Function

The regional distribution of skeletal muscle blood flow was measured during postischemic reactive hyperemia using Gd‐DTPA contrast‐enhanced (CE) MRI. The release of an occlusive thigh cuff was used to deliver a step‐input of contrast concentration that was coincident with the onset of reactive hyperemia. A first‐order tracer kinetic equation was used to estimate the unidirectional influx constant, Ki (ml/100 g/min), and the distribution volume of Gd‐DTPA in the tissue, ve, from T1‐weighted images acquired with saturation recovery (SR) steady‐state free precession (SSFP) and spoiled gradient‐echo (SPGR) protocols. The capillary permeability surface (PS) area increased significantly during reactive hyperemia, which facilitated rapid extraction of Gd‐DTPA during the first pass. Regional muscle group studies from 11 normal volunteers yielded blood flow (Ki) values of 108.3 ± 34.1 ml/100 g/min in the gastrocnemius, 184.3 ± 41.3 ml/100 g/min in the soleus, and 122.4 ± 34.4 ml/100 g/min in the tibialis anterior. The distribution volumes (ve) in the corresponding muscle groups were respectively 8.3% ± 2.1%, 9.3% ± 1.9%, and 7.9% ± 1.8% from the kinetic model, and 8.8% ± 2.4%, 9.1% ± 1.9%, and 7.2% ± 1.4% from tissue relaxometry studies. Bulk blood flow studies in the same volunteers using phase‐contrast velocimetry (popliteal artery) yielded significantly lower flow values, but with a correlation coefficient R2 = 0.62 and P = 0.004. Magn Reson Med 54:289–298, 2005. Published 2005 Wiley‐Liss, Inc.

Undersampled projection reconstruction for active catheter imaging with adaptable temporal resolution and catheter‐only views

In this study undersampled projection reconstruction (PR) was used for rapid catheter imaging in the heart, employing steady‐state free precession (SSFP) contrast. Active catheters and phased‐array coils were used for combined imaging of anatomy and catheter position in swine. Real‐time imaging of catheter position was performed with relatively high spatial and temporal resolution, providing 2 × 2 × 8 mm spatial resolution and four to eight frames per second. Two interactive features were introduced. The number of projections (Np) was adjusted interactively to trade off imaging speed and artifact reduction, allowing acquisition of high‐quality or high‐frame‐rate images. Thin‐slice imaging was performed, with interactive requests for thick‐slab projection images of the signal received solely from the active catheter. Briefly toggling on catheter‐only projection images was valuable for verifying that the catheter tip was contained within the selected slice, or for locating the catheter when part of it was outside the selected slice. Magn Reson Med 49:216–222, 2003. Published 2003 Wiley‐Liss, Inc.