Comparison of the myocardial clearance of endothelial progenitor cells injected early versus late into reperfused or sustained occlusion myocardial infarction.

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.

Hybrid SPECT/cardiac-gated first-pass perfusion CT: locating transplanted cells relative to infarcted myocardial targets.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Detection and quantification of myocardial reperfusion hemorrhage using T2*-weighted CMR.

OBJECTIVES: 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. BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: T2*-CMR accurately quantified myocardial reperfusion hemorrhage in vivo. Hemorrhage was associated with more severe infarct-related injury.

Comparison of initial cell retention and clearance kinetics after subendocardial or subepicardial injections of endothelial progenitor cells in a canine myocardial infarction model.

UNLABELLED: 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. METHODS: We evaluated 7 dogs with each technique, using (111)In-tropolone-labeled endothelial progenitor cells and serial SPECT/CT for 15 d after injection. RESULTS: 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. CONCLUSION: 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.