Biomedical subjects

Robert J Lederman

Publications and source records attributed to Robert J Lederman.

33 records · Page 2Linked to original sources

PubMed2004

Reduced field of view and undersampled PR combined for interventional imaging of a fully dynamic field of view.

Active catheter imaging was investigated using real-time undersampled projection reconstruction (PR) combined with the temporal filtering technique of reduced field of view (rFOV). Real-time rFOV processing was interactively enabled during highly undersampled catheter imaging, resulting in improved artifact suppression with better temporal resolution than that obtained by view-sharing. Imaging with 64 to 32 projections provided a resolution of 2 x 2 x 8 mm, and four to eight true frames per second. Image artifacts were reduced when rFOV processing was applied to the undersampled images. A comparison with Cartesian rFOV showed that PR image quality is less susceptible to aliasing that results from rFOV imaging with a wholly dynamic outer FOV. Simulations and MRI experiments demonstrated that PR rFOV provides significant artifact suppression, even for a fully dynamic FOV. The near doubling of temporal resolution that is possible with PR rFOV permits accurate monitoring of highly dynamic events, such as catheter movements, and arrhythmias, such as ventricular ectopy.

Animals↗

PubMed2004

Imaging of myocardial infarction for diagnosis and intervention using real-time interactive MRI without ECG-gating or breath-holding.

Current methods for MRI of infarcted myocardium require ECG-gating and breath-holding during contrast-enhanced segmented k-space inversion-recovery (IR) imaging. However, ECG-gating can be problematic in MRI, and breath-holding can be difficult for some patients. This work demonstrates that infarcted tissue can be visualized without ECG-gating or breath-holding with the use of intermittent inversion pulses during real-time (RT) interactive imaging with steady-state free precession (SSFP). The sequence generates a RT image stream containing a myocardium-nulled image every few frames, which allows nearly simultaneous observation of both infarcted regions and wall motion. First-pass perfusion and wall motion can be simultaneously observed with minor parameter modifications. This method may reduce diagnostic scan time, expand the target population, improve patient comfort, and facilitate targeted, interventional treatment of infarcted myocardium. Supplementary material for this article can be found on the MRM website at http://www.interscience.wiley.com/jpages/0740-3194/suppmat/index.html.

Animals↗

PubMed2003

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 1.7x3.3x8-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.

Animals↗

PubMed2003

Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, double-blind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication.

BACKGROUND: "Therapeutic angiogenesis" seeks to improve perfusion by the growth of new blood vessels. The Regional Angiogenesis with Vascular Endothelial growth factor (RAVE) trial is the first major randomized study of adenoviral vascular endothelial growth factor (VEGF) gene transfer for the treatment of peripheral artery disease (PAD). METHODS AND RESULTS: This phase 2, double-blind, placebo-controlled study was designed to test the efficacy and safety of intramuscular delivery of AdVEGF121, a replication-deficient adenovirus encoding the 121-amino-acid isoform of vascular endothelial growth factor, to the lower extremities of subjects with unilateral PAD. In all, 105 subjects with unilateral exercise-limiting intermittent claudication during 2 qualifying treadmill tests, with peak walking time (PWT) between 1 to 10 minutes, were stratified on the basis of diabetic status and randomized to low-dose (4x10(9) PU) AdVEGF121, high-dose (4x10(10) PU) AdVEGF121, or placebo, administered as 20 intramuscular injections to the index leg in a single session. The primary efficacy end point, change in PWT (DeltaPWT) at 12 weeks, did not differ between the placebo (1.8+/-3.2 minutes), low-dose (1.6+/-1.9 minutes), and high-dose (1.5+/-3.1 minutes) groups. Secondary measures, including DeltaPWT, ankle-brachial index, claudication onset time, and quality-of-life measures (SF-36 and Walking Impairment Questionnaire), were also similar among groups at 12 and 26 weeks. AdVEGF121 administration was associated with increased peripheral edema. CONCLUSIONS: A single unilateral intramuscular administration of AdVEGF121 was not associated with improved exercise performance or quality of life in this study. This study does not support local delivery of single-dose VEGF121 as a treatment strategy in patients with unilateral PAD.

Adenoviridae↗

PubMed2003

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 (10(4) to 10(6) cells/150 microL) 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 10(5) 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.

Animals↗

PubMed2003

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 x 2 x 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.

Animals↗

PubMed2003

Real-time accelerated interactive MRI with adaptive TSENSE and UNFOLD.

Reduced field-of-view (FOV) acceleration using time-adaptive sensitivity encoding (TSENSE) or unaliasing by Fourier encoding the overlaps using the temporal dimension (UNFOLD) can improve the depiction of motion in real-time MRI. However, increased computational resources are required to maintain a high frame rate and low latency in image reconstruction and display. A high-performance software system has been implemented to perform TSENSE and UNFOLD reconstructions for real-time MRI with interactive, on-line display. Images were displayed in the scanner room to investigate image-guided procedures. Examples are shown for normal volunteers and cardiac interventional experiments in animals using a steady-state free precession (SSFP) sequence. In order to maintain adequate image quality for interventional procedures, the imaging rate was limited to seven frames per second after an acceleration factor of 2 with a voxel size of 1.8 x 3.5 x 8 mm. Initial experiences suggest that TSENSE and UNFOLD can each improve the compromise between spatial and temporal resolution in real-time imaging, and can function well in interactive imaging. UNFOLD places no additional constraints on receiver coils, and is therefore more flexible than SENSE methods; however, the temporal image filtering can blur motion and reduce the effective acceleration. Methods are proposed to overcome the challenges presented by the use of TSENSE in interactive imaging. TSENSE may be temporarily disabled after changing the imaging plane to avoid transient artifacts as the sensitivity coefficients adapt. For imaging with a combination of surface and interventional coils, a hybrid reconstruction approach is proposed whereby UNFOLD is used for the interventional coils, and TSENSE with or without UNFOLD is used for the surface coils.

Animals↗

PubMed2003

Regional Angiogenesis with Vascular Endothelial Growth Factor (VEGF) in peripheral arterial disease: Design of the RAVE trial.

BACKGROUND: Patients with intermittent claudication caused by infrainguinal atherosclerosis have limited pharmacologic options "Therapeutic angiogenesis" is a novel treatment approach that seeks to improve perfusion of ischemic limbs by the induction of collateral vessel formation. This trial is a phase 2 randomized double-blind placebo-controlled proof of concept trial that will use an intramuscular adenoviral gene transfer approach of vascular endothelial growth factor, 121 isoform (Ad(GV)VEGF(121.10)) to patients with severe IC caused by infrainguinal disease. METHODS: This is a phase 2, double-blind, randomized, placebo-controlled, dose-finding, multicenter study. Patients with severe intermittent claudication caused by infrainguinal atherosclerosis predominantly involving the superficial femoral artery confirmed with imaging studies that meet inclusion criteria will be stratified on the basis of the presence or absence of diabetes mellitus and randomized in a 1:1:1 fashion to low dose (4 x 10(9) particle units), high dose (4 x 10(10) particle units), or placebo arms (35-36 patients per group). Subjects are required to have exercise-limiting IC in the index extremity during 2 qualifying exercise treadmill tests, with peak walking times between 1 and 10 minutes. A single dose of Ad(GV)VEGF(121.10) will be administered as 20 intramuscular injections throughout the area of the lower limb requiring collateralization. RESULTS: The primary efficacy parameter for the Regional Angiogenesis With Vascular Endothelial Growth Factor (RAVE) trial is the change in peak walking time at 12 weeks compared with baseline. The sample size is expected to provide an 80% power to detect a difference of 1.5 minutes between any of the 2 treatment groups and the placebo group. Secondary efficacy parameters include claudication onset time, hemodynamic effects of therapy assessed with ankle-brachial index, assessment of physical impairment, and health-related quality of life as measured with the Walking Impairment Questionnaire and SF-36 Health Survey. All randomized patients will also be evaluated for safety.

Adenoviridae↗

PubMed2003

Testing clinical therapeutic angiogenesis using basic fibroblast growth factor (FGF-2).

Therapeutic angiogenesis represents an attempt to relieve inadequate blood flow by the directed growth and proliferation of blood vessels. Neovascularization is a complex process involving multiple growth factors, receptors, extracellular matrix glycoproteins, intracellular and extracellular signaling pathways, and local and bone-marrow-derived constituent cells, all responding to a symphonic arrangement of temporal and spatial cues. In cardiovascular disease, patients with refractory angina and lower extremity intermittent claudication seem most amenable to early tests of therapeutic angiogenesis. Monotherapy with the recombinant protein basic fibroblast growth factor (FGF-2) has been tested in six human trials. These have shown provisional safety, and two have provided 'proof of concept' for the strategy of therapeutic angiogenesis. One large randomized phase II trial failed to show significant efficacy in coronary artery disease. Another showed significant efficacy in peripheral artery disease, although the magnitude of benefit was disappointing at the dose tested. This overview details the suitable clinical trial design and further steps toward the clinical development of FGF-2.

Clinical Trials, Phase I as Topic↗

PubMed2003

Percutaneous stenting of incidental unilateral renal artery stenosis: decision analysis of costs and benefits.

PURPOSE: To determine the incremental cost-effectiveness of prophylactic percutaneous transluminal angioplasty with stent placement (PTA-S) in patients with incidentally discovered, asymptomatic renal artery stenosis (RAS) compared to delaying PTA-S until patients develop refractory hypertension or renal insufficiency (therapeutic PTA-S). METHODS: The Markov decision analysis model was used to determine the incremental cost per quality adjusted life year (QALY) saved for prophylactic PTA-S as compared to therapeutic PTA-S in a hypothetical cohort of patients with 50% unilateral atherosclerotic RAS followed from age 61 to death. RESULTS: Prophylactic PTA-S compared to therapeutic PTA-S results in more QALYs/patient (10.9 versus 10.3) at higher lifetime costs ($23,664 versus $16,558). The incremental cost effectiveness of prophylactic PTA-S was estimated to be $12,466/QALY. Prophylactic stenting was not cost effective (>$50,000/QALY) if the modeled incidence of stent restenosis exceeded 15%/year and the incidence of progression in the contralateral renal artery was <2% of arteries/year. CONCLUSIONS: PTA-S of incidental, asymptomatic unilateral RAS may improve patients' quality of life at an acceptable incremental cost. However, this technology should be used hesitantly until a randomized comparison confirms its effectiveness.

Angioplasty, Balloon↗

PubMed2003

Intrinsic conflicts of interest in clinical research: a need for disclosure.

Protection of human subjects from investigators' conflicts of interest is critical to the integrity of clinical investigation. Personal financial conflicts of interest are addressed by university policies, professional society guidelines, public standards, and government regulation, but "intrinsic conflict of interest"--conflicts of interest inherent in all clinical research--have received relatively less attention. Such conflicts arise in all clinical research endeavors as a result of the tension among professionals' responsibilities to their research and to their patients and both academic and financial incentives. These conflicts should be disclosed to research subjects and managed as assiduously as are financial conflicts of interest.

Biomedical Research↗

PubMed2002

Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial.

BACKGROUND: Recombinant fibroblast growth factor-2 (rFGF-2) improves perfusion in models of myocardial and hindlimb ischaemia. We investigated whether one or two doses of intra-arterial rFGF-2 improves exercise capacity in patients with moderate-to-severe intermittent claudication. METHODS: 190 patients with intermittent claudication caused by infra-inguinal atherosclerosis were randomly assigned (1:1:1) bilateral intra-arterial infusions of placebo on days 1 and 30 (n=63); rFGF-2 (30 microg/kg) on day 1 and placebo on day 30 (single-dose, n=66); or rFGF-2 (30 microg/kg) on days 1 and 30 (double-dose, n=61). Primary outcome was 90-day change in peak walking time. Secondary outcomes included ankle-brachial pressure index and safety. The main analysis was per protocol. FINDINGS: Before 90 days, six patients had undergone peripheral revascularisation and were excluded, and ten withdrew or had missing data. 174 were therefore assessed for primary outcome. Peak walking time at 90 days was increased by 0.60 min with placebo, by 1.77 min with single-dose, and by 1.54 min with double-dose. By ANOVA, the difference between groups was p=0.075. In a secondary intention-to-treat analysis, in which all 190 patients were included, the difference was p=0.034. Pairwise comparison showed a significant difference between placebo and single-dose (p=0.026) but placebo and double-dose did not differ by much (p=0.45). Serious adverse events were similar in all groups. INTERPRETATION: Intra-arterial rFGF-2 resulted in a significant increase in peak walking time at 90 days; repeat infusion at 30 days was no better than one infusion. The findings of TRAFFIC provide evidence of clinical therapeutic angiogenesis by intra-arterial infusion of an angiogenic protein.

Aged↗

PubMed2002

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.

Animals↗

PubMed2002

Incomplete retention after direct myocardial injection.

Direct intramyocardial injection may permit local delivery of protein and gene therapy agents for myocardial and coronary artery disease. Little is known about the immediate fate of materials administered via percutaneous endomyocardial catheters or via surgical epicardial injection. In this study, we use a novel method to evaluate the acute retention of agents injected directly into the myocardium, compare epicardial with the percutaneous endocardial and postmortem delivery, and evaluate the influence of injectate volume on myocardial retention. Fifteen 40-50 kg pigs underwent overlapping myocardial injections using a percutaneous endomyocardial catheter, an epicardial needle via an open chest, and epicardial needle postmortem. Multiple distinct 15 micro neutron-activated microsphere species were used as tracers. Two or three myocardial walls were injected in each animal using 3.5 mm, 27-28 gauge needles at varying injectate volumes. Animals were sacrificed immediately. Myocardial walls were divided and multiple microsphere species were quantified. In an additional study, nine 70 kg pigs underwent percutaneous endomyocardial injections with replication-deficient adenovirus encoding for the production of lac-Z. The injectate volume was varied, while the viral particle number remained constant. The animals were sacrificed 5 days after the percutaneous injections; the heart, liver, and spleen were collected for beta-galactosidase activity. Endomyocardial injection was associated with 43% +/- 15% microsphere retention, compared with 15% +/- 21% (P < 0.01) retention of open chest epicardial injection and 89% +/- 60% (P < 0.01) for postmortem injection. Reducing the injectate volume from 100 to 10 microL improved microsphere retention (P = 0.01). There was a trend toward improved viral transfection associated with smaller injection volumes. Despite direct intramyocardial administration, a significant fraction of injectate is not retained locally. Catheter-based needle endomyocardial injection is associated with equivalent or superior injectate retention compared with open chest epicardial injection. Proportionately, more injectate may be retained at lower volumes. Loss may involve a combination of channel leakage, venous, and lymphatic return.

Adenoviridae↗

PubMed2002

Real-time volume rendered MRI for interventional guidance.

Volume renderings from magnetic resonance imaging data can be created and displayed in real-time with user interactivity. This can provide continuous 3D feedback to assist in guiding an interventional procedure. A system is presented which can produce real-time volume renderings from 2D multi-slice or 3D MR pulse sequences. Imaging frame rates up to 30 per second have been demonstrated with a latency of approximately one-third of a second, depending on the image matrix size. Several interactive capabilities have been implemented to enhance visualization such as cut planes, individual channel scaling and color highlighting, view sharing, saturation preparation, complex subtraction, gating control, and choice of alpha blending or MIP rendering. The system is described and some interventional application examples are shown. To view movies of some of the examples, enter the following address into a web browser: http://nhlbi.nih.gov/labs/papers/lce/guttman/rtvolmri/index/htm.

Animals↗