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Background: Myocardial infarction (MI) triggers a systemic inflammatory response which determines subsequent healing. Experimentally, cardiac positron emission tomography and magnetic resonance imaging have been used successfully to obtain mechanistic insights. We explored the translational potential in patients early after MI., Methods and Results: Positron emission tomography/computed tomography and cardiac magnetic resonance were performed in 15 patients <7 days after first MI. Cardiac magnetic resonance showed regional transmural late gadolinium enhancement and edema exceeding the area of late gadolinium enhancement. Using F-18 deoxyglucose with heparin pretreatment, metabolic rate of glucose (MRGlc) was significantly increased in infarct versus remote myocardium (median, 2.0 versus 0.4 mg/min per 100 mL; P=0.0001). MRGlc in infarct correlated with remote myocardium (ρ=0.64; P=0.01), spleen (ρ=0.82; P=0.0002), and bone marrow(ρ=0.57; P=0.03), but not with muscle or liver. Regionally, F-18 deoxyglucose score was highest in segments with late gadolinium enhancement versus edema only and remote (median, 2.0 versus 1.8 versus 0.4; P<0.0001). Patients requiring repeat intervention during preliminary follow-up of 11±5 months tended to have higher early post-MI MRGlc. Five patients with chronic, stable MI served as controls. Opposite to acute MI, MRGlc was lower in infarct (median infarct/remote ratio, 0.6 versus 3.2 for acute MI; P=0.001), and there was no correlation with bone marrow or spleen MRGlc., Conclusions: Increased glucose utilization after heparin-induced suppression of myocyte uptake appears to mostly reflect inflammatory activity in damaged myocardium early after MI. Consistent with prior preclinical observations, and in contrast to chronic MI, this is associated with activity in spleen and bone marrow as sources of inflammatory cells. Positron emission tomography and cardiac magnetic resonance multimodality characterization of the acutely infarcted, inflamed myocardium may provide multiparametric end points for clinical studies aiming at support of infarct healing., (© 2014 American Heart Association, Inc.)

Erythropoietin (EPO) was shown to have protective effects after myocardial infarction (MI) by neovascularization and antiapoptotic mechanisms. Beside direct receptor-dependent mechanisms, mobilization and homing of bone marrow-derived cells (BMCs) may play a pivotal role in this regard. In this study, we intended to track different subpopulations of BMCs and to assess serially myocardial perfusion changes in EPO-treated mice after MI. To allow tracking of BMCs, we used a chimeric mouse model. Therefore, mice (C57BL/6J) were sublethally irradiated, and bone marrow (BM) from green fluorescent protein transgenic mice was transplanted. Ten weeks later coronary artery ligation was performed to induce MI. EPO was injected for 3 days with a total dose of 5000 IU/kg. Subpopulations (CD31, c-kit, CXCR-4 and Sca-1) of EGFP(+) cells were studied in peripheral blood, bone marrow and hearts by flow cytometry. Myocardial perfusion was serially investigated in vivo by pinhole single-photon emission computed tomography (SPECT) at days 6 and 30 after MI. EPO-treated animals revealed an enhanced mobilization of BMCs into peripheral blood. The numbers of these cells in BM remained unchanged. Homing of all BMCs subpopulations to the ischaemic myocardium was significantly increased in EPO-treated mice. Among the investigated subpopulations, EPO predominantly affected migration of CXCR-4(+) (4.3-fold increase). Repetitively SPECT analyses revealed a reduction of perfusion defects after EPO treatment over time. Our study shows that EPO treatment after MI enhances the migration capacity of BMCs into ischaemic tissue, which may attribute to an improved perfusion and reduced size of infarction, respectively., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

Background: G-CSF based stem cell mobilization and stabilization of cardiac SDF-1 by DPP-IV-inhibition (dual stem cell therapy) improve heart function and survival after myocardial infarction. However, it is barely understood whether this new approach acts specifically through the SDF-1/CXCR4 axis, stimulation of resident cardiac stem cells and improved myocardial perfusion. Therefore, we aimed to clarify the role of the SDF1/CXCR4 axis with respect to the benefits of a dual stem cell based therapy., Methodology/principal Findings: After surgically induced ligation of the LAD, SDF-1/CXCR4 interactions were specifically blocked by the CXCR4 receptor antagonist AMD3100 in G-CSF and Diprotin A treated C57BL/6 mice. G-CSF+DipA treated and non-treated animals served as controls. Because AMD3100 is known to mobilize bone marrow derived stem cells (BMCs) in high concentrations, the optimal dosage (1.25mg per kg body weight) sufficient to block CXCR4 without stimulating mobilization was established. AMD3100 treatment of G-CSF and Diprotin A stimulated mice significantly decreased myocardial homing of circulating stem cells (FACS analysis) and inverted the beneficial effects of (i) cardiac remodeling (histological analyses), (ii) heart function (Millar tip catheterization) and (iii) survival (Kaplan-Meier curves). G-CSF treatment in combination with DPP-IV inhibition enhanced neovascularization at the infarct border zone which was related to an improved myocardial blood flow as measured by SPECT. Moreover, dual stem cell treatment effectively stimulated the pool of resident cardiac stem cells (FACS) which was reversed by AMD3100 treatment., Conclusions/significance: Our data give final proof that homing through the SDF-1/CXCR-4 axis is essential for the success of dual stem cell therapy., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Introduction: The aim of this study is to evaluate a non-invasive method for measuring myocardial perfusion defect size in mice using a clinical single-photon emission computed tomography system equipped with pinhole collimators (pinhole SPECT)., Materials and Methods: Thirty days after ligation of the left anterior descending coronary artery, 13 mice (C57BL/6J) were imaged following intravenous injection of 370 MBq [99mTc]sestamibi. Eight control mice without myocardial infarction were likewise investigated. Image quality optimization had been achieved by repeated scanning of a multiple point phantom, with varying zoom factors, number of projection angles, and pinhole diameter. Volumetric sampling was used to generate polar maps, in which intensity was normalized to that of a standard septal region of interest (ROI), which was set at 100%. Receiver operating characteristic analyses were performed to define an optimal threshold as compared to histologically measured defect sizes, which were considered as gold standard., Results: A spatial resolution of 1.9 mm was achieved using a pinhole diameter of 0.5 mm, a zoom factor of 2, and 6 degrees projection angles. Histological results were best reproduced by a 60% threshold relative to the septal reference ROI. By applying this threshold, SPECT perfusion defect sizes revealed very high correlation to the histological results (R(2) = 0.867) with excellent intra- and interobserver reproducibility (intraclass correlation coefficients of 0.84 and 0.82)., Conclusions: We achieved a spatial resolution of 1.9 mm in myocardial perfusion imaging in mice using a clinical SPECT system mounted with pinhole collimators. Compared to a histological gold standard, the infarct sizes were accurately estimated, indicating that this method shows promise to monitor experimental cardiac interventions in mice.

Mobilization of stem cells by granulocyte colony-stimulating factor (G-CSF) was shown to have protective effects after myocardial infarction (MI); however, clinical trials failed to be effective. In search for alternative cytokines, parathyroid hormone (PTH) was recently shown to promote cardiac repair by enhanced neovascularization and cell survival. To compare the impact of the two cytokines G-CSF and PTH on myocardial perfusion, mice were noninvasively and repetitively investigated by pinhole single-photon emission computed tomography (SPECT) after MI. Mobilization and homing of bone marrow-derived stem cells (BMCs) was analyzed by fluorescence-activated cell sorter (FACS) analysis. Mice (C57BL/6J) were infarcted by left anterior descending artery ligation. PTH (80 mug/kg) and G-CSF (100 mug/kg) were injected for 5 days. Perfusion defects were determined by (99m)Tc-sestamibi SPECT at days 6 and 30 after MI. The number of BMCs characterized by Lin(-)/Sca-1(+)/c-kit(+) cells in peripheral blood and heart was analyzed by FACS. Both G-CSF and PTH treatment resulted in an augmented mobilization of BMCs in the peripheral blood. Contrary to G-CSF and controls, PTH and the combination showed significant migration of BMCs in ischemic myocardium associated with a significant reduction of perfusion defects from day 6 to day 30. A combination of both cytokines had no additional effects on migration and perfusion. In our preclinical model, SPECT analyses revealed the functional potential of PTH reducing size of infarction together with an enhanced homing of BMCs to the myocardium in contrast to G-CSF. A combination of both cytokines did not improve the functional outcome, suggesting clinical applications of PTH in ischemic heart diseases.