[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
Inflammation that occurs after acute myocardial infarction plays a pivotal role in healing by facilitating the creation of a supportive scar. (18)F-FDG, which is taken up avidly by macrophages, has been proposed as a marker of cell-based inflammation. However, its reliability as an accurate indicator of inflammation has not been established, particularly in the early postinfarction period when regional myocardial perfusion is often severely compromised.
Nine adult dogs underwent left anterior descending coronary occlusion with or without reperfusion. Animals were imaged between 7 and 21 d after infarction with PET/MR imaging after bolus injection of gadolinium-diethylenetriaminepentaacetic acid (DTPA), bolus injection of (18)F-FDG, bolus injection of (99)Tc-DTPA to simulate the distribution of gadolinium-DTPA (which represents its partition coefficient in well-perfused tissue), and injection of (111)In-labeled white blood cells 24 h earlier. After sacrifice, myocardial tissue concentrations of (18)F, (111)In, and (99)Tc were determined in a well counter. Linear regression analysis evaluated the relationships between the concentrations of (111)In and (18)F and the dependence of the ratio of (111)In/(18)F to the apparent distribution volume of (99m)Tc-DTPA.
In 7 of 9 animals, (111)In increased as (18)F increased with the other 2 animals, showing weak negative slopes. With respect to the dependence of (111)In/(18)F with partition coefficient, 4 animals showed no dependence and 4 showed a weak positive slope, with 1 animal showing a negative slope. Further, in regions of extensive microvascular obstruction, (18)F significantly underestimated the extent of the presence of (111)In.
In the early post-myocardial infarction period, (18)F-FDG PET imaging after a single bolus administration may underestimate the extent and degree of inflammation within regions of microvascular obstruction.
Preview · Article · Jan 2015 · Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: Stem cell transplantation following AMI has shown promise for the repair or reduction of the amount of myocardial injury. There is some evidence that these treatment effects appear to be directly correlated to cell residence time. This study aims to assess the effects of (a) the timing of stem cell injection following myocardial infarction, and (b) flow milieu, on cell residence times at the site of transplantation by comparing three time points (day of infarction, week 1 and week 4-5), and two models of acute myocardial infarction (sustained occlusion or reperfusion). Twenty-one dogs received 2 injections of 30 million endothelial progenitor cells. The first injections were administered by epicardial (n = 8) or endocardial injection (n = 13) either on the day of infarction (n = 15) or at 1 week (n = 6). The second injections were administered by only endocardial injection (n = 18) 4 weeks following the first injection. Cell clearance half-lives were comparable between early and late injections. However, transplants into sustained occlusion infarcts resulted in slower cell clearance 77.1 ± 6.1 (n = 18) versus reperfused 59.4 ± 2.9 h (n = 21) p = 0.009. Sustained occlusion infarcts had longer cell retention in comparison to reperfusion whereas the timing of injection did not affect clearance rates. If the potential for myocardial regeneration associated with cell transplantation is, at least in part, linked to cell residence times, then greater benefit may be observed with transplants into infarcts associated with persistent coronary artery occlusion.
Full-text · Article · Jun 2012 · The international journal of cardiovascular imaging
[Show abstract][Hide abstract] ABSTRACT: A challenge with cardiac cell therapy is determining the location of cells relative to infarct tissue. As cells are viable following ¹¹¹In-labeling, and first-pass CT imaging can identify regions of myocardial infarction, we evaluated the feasibility of a SPECT/CT system to localize cells relative to infarcted myocardium in a canine model.
Ten canines underwent surgical ligation of the left-anterior-descending artery and endothelial progenitor cells labeled with ¹¹¹In-tropolone were transplanted endocardially or epicardially. SPECT/CT was performed on day of transplantation, 4 and 10 days post-transplantation. For each imaging session first-pass perfusion CT was performed to delineate the area of reduced perfusion. SPECT and first-pass CT images were fused and evaluated. Contrast-to-noise ratios (CNR) were calculated for ¹¹¹In-SPECT images to evaluate cell detection.
The zone of reduced perfusion was well delineated on first-pass perfusion CT in all canines. The ¹¹¹In signal was visualized within this zone in all cases. Analysis of the CNRs suggests that cells may be followed for 11 effective half-lives using the images from first-pass perfusion CT to provide the anatomic landmarks.
In the setting of an acute myocardial infarction SPECT/[first-pass perfusion CT] is an effective hybrid platform for the localization of cells in relation to the area of reduced blood flow.
No preview · Article · Jan 2012 · Contrast Media & Molecular Imaging
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to validate T2*-weighted cardiac magnetic resonance (T2*-CMR) for the detection and quantification of reperfusion hemorrhage in vivo against an ex vivo gold standard, and to investigate the relationship of hemorrhage to microvascular obstruction, infarct size, and left ventricular (LV) functional parameters.
Hemorrhage can contribute to reperfusion injury in myocardial infarction and may have significant implications for patient management. There is currently no validated imaging method to assess reperfusion hemorrhage in vivo. T2*-CMR appears suitable because it can create image contrast on the basis of magnetic field effects of hemoglobin degradation products.
In 14 mongrel dogs, myocardial infarction was experimentally induced. On day 3 post-reperfusion, an in vivo CMR study was performed including a T2*-weighted gradient-echo imaging sequence for hemorrhage, standard sequences for LV function, and post-contrast sequences for microvascular obstruction and myocardial necrosis. Ex vivo, thioflavin S imaging and triphenyl-tetrazoliumchloride (TTC) staining were performed to assess microvascular obstruction, hemorrhage, and myocardial necrosis. Images were analyzed by blinded observers, and comparative statistics were performed.
Hemorrhage occurred only in the dogs with the largest infarctions and the greatest extent of microvascular obstruction, and it was associated with more compromised LV functional parameters. Of 40 hemorrhagic segments on TTC staining, 37 (92.5%) were positive for hemorrhage on T2*-CMR (kappa = 0.96, p < 0.01 for in vivo/ex vivo segmental agreement). The amount of hemorrhage in 13 affected tissue slices as determined by T2*-CMR in vivo correlated strongly with ex vivo results (20.3 ± 2.3% vs. 17.9 ± 1.6% per slice; Pearson r = 0.91; r(2) = 0.83, p < 0.01 for both). Hemorrhage size was not different between in vivo T2*-CMR and ex vivo TTC (mean difference 2.39 ± 1.43%; p = 0.19).
T2*-CMR accurately quantified myocardial reperfusion hemorrhage in vivo. Hemorrhage was associated with more severe infarct-related injury.
Full-text · Article · Dec 2011 · JACC. Cardiovascular imaging
[Show abstract][Hide abstract] ABSTRACT: Introduction. Previously we proposed a cellular imaging technique to determine the surviving fraction of transplanted cells in vivo. Epicardial kinetics using Indium-111 determined the Debris Impulse Response Function (DIRF) and leakage coefficient parameters. Convolution-based modeling which corrected for these signal contributions indicated that 111In activity was quantitative of cell viability with half-lives within 20 hrs to 37 days. We determine if the 37-day upper limit remains valid for endocardial injections by comparing previous epicardial cell leakage parameter estimates to those for endocardial cells. Methods. Normal canine myocardium was injected (111In-tropolone) epicardially (9 injections) or endocardially (10 injections). Continuous whole body and SPECT scans for 5 hours were acquired with three weekly follow-up imaging sessions up to 20–26 days. Time-activity curves evaluated each injection type. Results. The epicardial and endocardial kinetics were not significantly different (Epi: 1286 ± 253; Endo: 1567 ± 470 hours P = .62).
Conclusion. The original epicardial estimate of leakage kinetics has been validated for use in endocardial injections.
[Show abstract][Hide abstract] ABSTRACT: Neither intravenous nor intracoronary routes provide targeted stem cell delivery to recently infarcted myocardium in sufficient quantities. Direct routes appear preferable. However, most prior studies have used epicardial injections, which are not practical for routine clinical use. The objective of this study was to compare cell retention and clearance kinetics between a subepicardial and a subendocardial technique.
We evaluated 7 dogs with each technique, using (111)In-tropolone-labeled endothelial progenitor cells and serial SPECT/CT for 15 d after injection.
In vivo indium imaging demonstrated comparable degrees of retention: 57% +/- 15% for the subepicardial injections and 54% +/- 26% for the subendocardial injections. Clearance half-lives were also similar at 69 +/- 26 and 60 +/- 21 h, respectively.
This study demonstrates that subendocardial injections, clinically more practical, show clearance kinetics comparable to those of subepicardial injections and will facilitate the ultimate clinical use of this treatment modality.
No preview · Article · Feb 2010 · Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: Purpose: Previous studies have shown the ability of rubidium-82 (82Rb) positron emission tomography (PET) imaging to quantitatively measure myocardial blood flow (MBF), many of which are performed using two-dimensional (2D) imaging. Three-dimensional (3D) imaging provides increased sensitivity and may result in decreased costs owing to a reduction in the required injected activity of radiotracer. This study compares 2D and 3D 82Rb PET MBF results obtained in the same imaging session.
Methods: Three-dimensional and 2D 82Rb perfusion imaging was performed in canines on a GE Discovery LS PET/CT scanner at rest and during hyperemia in stunned and infarcted tissue. MBF (ml/min/g) was determined using a 1-compartment model and an extraction correction of the uptake rate and analyzed using a standard 17-segment model.
Results: A strong, significant correlation was present (ρ = 0.95, P<0.0001). Average 3D MBF values were slightly lower at rest and higher during stress versus 2D. MBF results in normal, stunned, and infarcted tissue differed by 7% on average and significant increases in MBF from rest to hyperemia were noted with both the techniques.
Conclusion: These results imply that MBF results obtained in 3D are comparable with traditional 2D imaging. Therefore, it may be possible to use 3D imaging with lower administered activity, helping to reduce costs and patient dose without compromising quantitative information.
No preview · Article · Dec 2009 · Nuclear Medicine Communications
[Show abstract][Hide abstract] ABSTRACT: Myocardial viability and quantification of regional myocardial blood flow (MBF) are important for the diagnosis of heart disease. Positron emission tomography is the current gold standard for determining myocardial viability, but most positron-emitting perfusion tracers require an on-site cyclotron. Rubidium-82 ((82)Rb) is a myocardial perfusion tracer that is produced using an on-site generator. This study investigates (82)Rb-measured MBF in canine models of stunned and infarcted myocardium compared with selected measurements obtained concurrently using microspheres.
Myocardial stunning and infarction were created in canines by occluding the left anterior descending for 15 min and 2 h, respectively. Stunning was produced in all animals; six animals were reperfused after the 2 h occlusion, whereas the other six animals remained occluded permanently. Regional MBF was measured in each group during rest and dobutamine stress at acute and chronic (8 weeks postinsult) time points using dynamic (82)Rb perfusion imaging and radioactively labeled microspheres.
Average resting MBF with microspheres and Rb was 0.68+/-0.02 versus 0.73+/-0.01 (P<0.001) in nonischemic tissue, and 0.53+/-0.03 versus 0.42+/-0.02 (P<0.001) in the region-at-risk tissue, respectively. Average MBF during stress with microspheres and Rb was 2.78+/-0.15 versus 3.53+/-0.16 (P<0.05) in the nonischemic tissue, and 1.90+/-0.20 versus 2.31+/-0.26 (P = NS) in the region-at-risk tissue, respectively.
Despite the small significant differences, the dynamic (82)Rb measurements provide estimates of MBF in stunned and acutely and chronically infarcted tissue at rest and during hyperemia that correspond with clinical interpretation.
No preview · Article · Oct 2009 · Nuclear Medicine Communications
[Show abstract][Hide abstract] ABSTRACT: Current investigations of cell transplant therapies in damaged myocardium are limited by the inability to quantify cell transplant survival in vivo. We describe how the labeling of cells with (111)In can be used to monitor transplanted cell viability in a canine infarction model.
We experimentally determined the contribution of the (111)In signal associated with transplanted cell (TC) death and radiolabel leakage to the measured SPECT signal when (111)In-labeled cells were transplanted into the myocardium. Three groups of experiments were performed in dogs. Radiolabel leakage was derived by labeling canine myocardium in situ with free (111)In-tropolone (n = 4). To understand the contribution of extracellular (111)In (e.g., after cell death), we developed a debris impulse response function (DIRF) by injecting lysed (111)In-labeled cells within reperfused (n = 3) and nonreperfused (n = 5) myocardial infarcts and within normal (n = 3) canine myocardium. To assess the application of the modeling derived from these experiments, (111)In-labeled cells were transplanted into infarcted myocardium (n = 4; 3.1 x 10(7) +/- 5.4 x 10(6) cells). Serial SPECT images were acquired after direct epicardial injection to determine the time-dependent radiolabel clearance. Clearance kinetics were used to correct for (111)In associated with viable TCs.
(111)In clearance followed a biphasic response and was modeled as a biexponential with a short (T(1/2)(s)) and long (T(1/2)(l)) biologic half-life. The T(1/2)(s) was not significantly different between experimental groups, suggesting that initial losses were due to transplantation methodology, whereas the T(1/2)(l) reflected the clearance of retained (111)In. DIRF had an average T(1/2)(l) of 19.4 +/- 4.1 h, and the T(1/2)(l) calculated from free (111)In-tropolone injected in situ was 882.7 +/- 242.8 h. The measured T(1/2)(l) for TCs was 74.3 h and was 71.2 h when corrections were applied.
A new quantitative method to assess TC survival in myocardium using SPECT and (111)In has been introduced. At the limits, method accuracy is improved if appropriate corrections are applied. In vivo (111)In imaging most accurately describes cell viability half-life if T(1/2)(l) is between 20 h and 37 d.
No preview · Article · Jul 2009 · Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: The clinical application of stem cell therapy for myocardial infarction will require the development of methods to monitor treatment and pre-clinical assessment in a large animal model, to determine its effectiveness and the optimum cell population, route of delivery, timing, and flow milieu.
To establish a model for a) in vivo tracking to monitor cell engraftment after autologous transplantation and b) concurrent measurement of infarct evolution and remodeling.
We evaluated 22 dogs (8 sham controls, 7 treated with autologous bone marrow monocytes, and 7 with stromal cells) using both imaging of 111Indium-tropolone labeled cells and late gadolinium enhancement CMR for up to12 weeks after a 3 hour coronary occlusion. Hearts were also examined using immunohistochemistry for capillary density and presence of PKH26 labeled cells.
In vivo Indium imaging demonstrated an effective biological clearance half-life from the injection site of ~5 days. CMR demonstrated a pattern of progressive infarct shrinkage over 12 weeks, ranging from 67-88% of baseline values with monocytes producing a significant treatment effect. Relative infarct shrinkage was similar through to 6 weeks in all groups, following which the treatment effect was manifest. There was a trend towards an increase in capillary density with cell treatment.
This multi-modality approach will allow determination of the success and persistence of engraftment, and a correlation of this with infarct size shrinkage, regional function, and left ventricular remodeling. There were overall no major treatment effects with this particular model of transplantation immediately post-infarct.
Full-text · Article · May 2009 · Journal of Cardiovascular Magnetic Resonance
[Show abstract][Hide abstract] ABSTRACT: Introduction: Reperfusion injury in myocardial infarction leads to microvascular obstruction, which can occur with or without gross reperfusion hemorrhage. The incidence and implications of reperfusion hemorrhage are not well investigated. A recently described in vivo imaging approach using T2*-weighted cardiovascular magnetic resonance can help investigate the pathophysiology of reperfusion hemorrhage in vivo.Hypothesis: We hypothesized that hemorrhage reflects a severer from of reperfusion injury and therefore occurs with larger infarct size and worse LV function as compared to reperfusion injury without hemorrhage.Methods: In 14 female mongrel dogs, myocardial infarction was induced by ligation of the left anterior descending coronary artery for 2–4 hours, followed by reperfusion. On day 3 ± 1, a cardiovascular magnetic resonance study was performed in vivo to (1) assess presence of microvascular obstruction, defining reperfusion injury (2) assess presence of reperfusion hemorrhage (3) quantify left ventricular end-diastolic volume, ejection fraction and cardiac output and (4) quantify infarct size with late enhancement. An independent-samples t-test was performed to compare these parameters in dogs with and without hemorrhage in reperfusion injury.Results: From 14 dogs, 9 had microvascular obstruction, and 4/9 had reperfusion hemorrhage in addition to microvascular obstruction.Dogs with hemorrhagic infarcts had significantly larger infarct size (26.1 ± 6.6 g vs. 5.5 ± 3.9 g, p < 0.05), lower LV ejection fraction (28 ± 7% vs. 53 ± 12%, p < 0.05), and lower cardiac output (1.9 ± 0.2 l/min vs. 2.8 ± 0.5 l/min, p < 0.05). There were no differences in LV end-diastolic volume and LV mass.Discussion and conclusion: In this dog model of ischemia/reperfusion injury, gross hemorrhage was associated with significantly larger infarct size and worse LV functional parameters. This supports the hypothesis that hemorrhage may occur with advanced, severe ischemic tissue injury only.
Preview · Article · Jan 2009 · Journal of Cardiovascular Magnetic Resonance
[Show abstract][Hide abstract] ABSTRACT: To evaluate qualitative wall motion assessment vs. quantitative wall thickening for the assessment of subtle changes in myocardial systolic function using cine MRI.
Cine MR images were obtained in 5 canines with a significant coronary artery stenosis and in 2 controls on a 1.5T scanner. Qualitative results were obtained using a numerical scoring system; quantitative analysis was performed using a semi-automatic segmentation program. The techniques were matched and compared using Spearman correlations.
All correlations in the experimental group revealed significant but weak to moderate relationships between the qualitative and quantitative results (e.g., at-risk tissue rho = 0.363, p < 0.0001; remote tissue rho = 0.275, p = 0.0002), with each identifying changes in regional function that ensued following creation of the stenosis. Intra-observer variability was reasonable in both methods when repeat analysis on a subset of the data was performed, with both techniques showing a significant correlation between the repeated measurements (quantitative - rho = 0.52, p < 0.0001; qualitative - rho = 0.54, p < 0.0001).
Both methods were able to detect very limited wall motion abnormalities present in the canines with significant stenosis and either method gives comparable results.
No preview · Article · Feb 2006 · Journal of Cardiovascular Magnetic Resonance
[Show abstract][Hide abstract] ABSTRACT: In this work, we determined the minimum number of detectable 111In-tropolone-labelled bone-marrow-derived stem cells from the maximum activity per cell which did not affect viability, proliferation and differentiation, and the minimum detectable activity (MDA) of 111In by SPECT. Canine bone marrow mesenchymal cells were isolated, cultured and expanded. A number of samples, each containing 5x10(6) cells, were labelled with 111In-tropolone from 0.1 to 18 MBq, and cell viability was measured afterwards for each sample for 2 weeks. To determine the MDA, the anthropomorphic torso phantom (DataSpectrum Corporation, Hillsborough, NC) was used. A point source of 202 kBq 111In was placed on the surface of the heart compartment, and the phantom and all compartments were then filled with water. Three 111In SPECT scans (duration: 16, 32 and 64 min; parameters: 128x128 matrix with 128 projections over 360 degrees) were acquired every three days until the 111In radioactivity decayed to undetectable quantities. 111In SPECT images were reconstructed using OSEM with and without background, scatter or attenuation corrections. Contrast-to-noise ratio (CNR) in the reconstructed image was calculated, and MDA was set equal to the 111In activity corresponding to a CNR of 4. The cells had 100% viability when incubated with no more than 0.9 MBq of 111In (80% labelling efficiency), which corresponded to 0.14 Bq per cell. Background correction improved the detection limits for 111In-tropolone-labelled cells. The MDAs for 16, 32 and 64 min scans with background correction were observed to be 1.4 kBq, 700 Bq and 400 Bq, which implies that, in the case where the location of the transplantation is known and fixed, as few as 10,000, 5000 and 2900 cells respectively can be detected.
No preview · Article · Nov 2005 · Physics in Medicine and Biology
[Show abstract][Hide abstract] ABSTRACT: MRI after a constant infusion (CI) of Gd-DTPA has been used to identify the extent of myocardial infarction (MI). However, Gd-DTPA-enhanced "viability" imaging is more commonly performed with a bolus (for "delayed-enhancement" (DE) imaging). This study sought to determine how image delay time and time postinfarction influence the assessment of necrosis by DE. Both infusion and DE imaging was performed in dogs with reperfused (N = 6) or unreperfused (N = 4) MI. Estimates of the partition-coefficient of Gd-DTPA (lambda) with DE were compared with those calculated after 60 min of infusion, and the comparisons were repeated until 4 (reperfused) or 8 (unreperfused) weeks postinfarction. In reperfused animals, the concordance (Rc) between DE and infusion estimates of lambda was > 0.90 for most image delays > 8 min postinjection, for day 0 through week 3, with Rc at day 0 greater than at week 4 (P = 0.022). In unreperfused animals, there was an interaction between image delay time and time postinfarction (P < 0.001): Rc > 0.90 corresponded to longer image delays at week 1 than at weeks 4-8. Therefore, when image delays are selected appropriately, DE images can strongly reflect lambda and identify irreversibly injured myocardium.
Full-text · Article · Nov 2004 · Magnetic Resonance in Medicine
[Show abstract][Hide abstract] ABSTRACT: The underlying assumption in delayed enhancement or constant infusion techniques to detect infarcted myocardium is that the partition coefficient (lambda) of Gd-DTPA only increases in permanently damaged tissue. This assumption is supported in canine models of stunned and infarcted myocardium but has not been adequately tested in models of chronic, reversibly damaged tissue.
A significant coronary stenosis was maintained for 3 (n = 9) or 10 (n = 4) weeks in a canine model. Myocardial perfusion was assessed using radioactively labeled microspheres, and Doppler flow was used to monitor the effect on flow caused by the stenosis formation. Function and in vivo lambda were assessed using magnetic resonance imaging (MRI) and a constant infusion of Gd-DTPA. 201Tl and 111In-DTPA were used to assess ex vivo myocardial viability and lambda, respectively.
Baseline Doppler-measured blood flow through the left anterior descending coronary artery was reduced by 72.4 +/- 1.6% (SEM) during the stenosis formation. However, shortly after creation of the stenosis and at sacrifice, regional myocardial blood flow at rest was not decreased in the Region at Risk (RAR) despite the persistence of the stenosis. Perfusion reserve in this model, measured using adenosine stress, was significantly reduced. The in vivo lambda values in the RAR and remote tissue ranged between 0.32-0.45 mL/g and 0.31-0.42 mL/g, respectively. 201Tl uptake was maintained in all tissue, confirming the maintenance of tissue viability. Global function was unchanged while regional function was significantly depressed at 10 days but returned to baseline values by day 21.
This study is consistent with the hypothesis that lambda is not increased in reversibly dysfunctional myocardium.
Full-text · Article · Feb 2004 · Journal of Cardiovascular Magnetic Resonance
[Show abstract][Hide abstract] ABSTRACT: Using both 31P and 1H cardiac magnetic resonance techniques, it is possible to monitor the functional (ejection fraction [EF]) and biochemical (pH) status of the heart following a reperfused ischemic insult. This study assessed the effects of Na+/H+ exchange inhibition with cariporide in a closed-chest canine ischemia/reperfusion model. Dogs received 1-mg/kg cariporide treatments for 3 days after occlusion, but were monitored for 10 days. Baseline intracellular pH (+/-SEM) for the control and treated groups were 7.10 +/- 0.03 and 7.14 +/- 0.04, respectively, and dropped to 6.25 +/- 0.08 and 6.38 +/- 0.08 during occlusion. There was a significant increase in pH from occlusion to early reperfusion in the control group (P = 0.03) but, during the same time period, this increase was not seen in the cariporide group. There was a significant (P = 0.01) drug interaction in recovery of EF over the 10-day protocol. Individual time-point analysis revealed significant differences at immediate reperfusion through day 3 (73.9% +/- 2.5%, 84.5% +/- 3.1%; baseline normalized EF controls and cariporide, respectively). Neither pH nor EF measurements were significantly different between the groups at day 10. Despite early functional and metabolic benefits, infarct size, as measured at day 10, was 13.2% +/- 2.2% for the controls and 11.8% +/- 2.3% for the cariporide group (NS). Thus there were no long-term cariporide functional or biochemical benefits.
No preview · Article · May 2003 · Journal of Cardiovascular Pharmacology