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Contrast-enhanced MRI tracking of post-infarct myocardial macrophage infiltration
ABSTRACTS / Journal of Molecular and Cellular Cardiology 40 (2006) 920 – 1015
001. Supra-normal (phospho-)creatine levels lead to heart failure in mice overexpressing the cardiac creatine transporter—a longitudinal study Michiel ten Hove, Darci Phillips, Julie Wallis, Craig A. Lygate, Alexandra Fischer, Liam Sebag-Montefiore, Dana Dawson, Karen Hulbert, Wen Zhang, Hugh Watkins, Kieran Clarke, Ju¨rgen E. Schneider, Stefan Neubauer. University of Oxford, UK In heart failure, myocardial creatine (Cr) levels are reduced due to reduced capacity of the myocardial creatine transporter (CrT), possibly contributing to contractile dysfunction. Increasing Cr levels therefore could be beneficial. Increased plasma levels in vivo, however, result in downregulation of the myocardial CrT. In order to increase myocardial Cr levels, we created a transgenic mouse overexpressing the myocardial CrT (CrT-OE). Compared to wild-type littermate controls (WT), myocardial creatine levels (HPLC) were increased in CrT-OE hearts (66 T 6 in WT vs. 133 T 52 nmol/mg protein in CrT-OE). Phosphocreatine (PCr) levels, measured by 31P MRS in isolated hearts, were also increased but to a lesser extent. Surprisingly, CrT-OE mice developed substantial LV dysfunction (3D-echo, MRI). Myocardial creatine content correlated closely with EF (r = 0.74, P = 0.0002), LVEDP (r = 0.52, P = 0.02) and dP/dtmax (r = 0.69, P = 0.0008). In spite of increased (P)Cr levels, CrTOE hearts showed increased [ADP]free and reduced free energy change for ATP hydrolysis. The accumulation of Cr and the development of heart failure were studied over time using in vivo 1H MRS and MRI to measure cardiac Cr and function, respectively. Mice were subjected to multiple measurements at 6 weeks, 4 months and 8 months of age, respectively. Results showed that the development of heart failure was preceded by the accumulation of creatine in the heart, being consistent with a causal relation. Overexpression of the cardiac CrT results in accumulation of myocardial Cr, followed by the development of heart failure. doi:10.1016/j.yjmcc.2006.03.016
002. Contrast-enhanced MRI tracking of post-infarct myocardial macrophage infiltration A.F. Catchpole, C.A. Carr, J.E. Schneider, D.J. Tyler, D.J. Stuckey, K. Clarke. Cardiac Metabolism Research Group, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, UK Cardiac inflammation following an infarction may contribute to the development of heart failure. We aimed to track macrophage infiltration into the infarcted heart using noninvasive in vivo magnetic resonance imaging (MRI) knowing that blood monocytes endocytose superparamagnetic iron oxide particles (SPIOs), which create signal voids in the MR images. We postulated that the monocytes would home to infarct sites and differentiate into macrophages. Methods: Wistar rats were subjected to left coronary artery ligation. SPIOs (250 Amol Fe/kg bodyweight) were injected
921
after 1, 3 or 6 days. Macrophage infiltration was monitored by T2*-weighted MRI and ex vivo MR microscopy. C-reactive protein and Troponin-I were measured by ELISA. Results: Regions of hypointensity were detected in the damaged region of infarcted hearts in animals injected on days 3 and 6 and these were still visible at day 20. There were no signal voids observed in sham-operated animals or those injected with SPIOs on day 1, indicating that blood monocytes were not present for at least 24 h after infarction. Ejection fractions negatively correlated with the percentage of akinetic myocardium and signal void volumes. The presence of SPIOs in the myocardium was confirmed by MR microscopy. At 1– 2 days post-surgery, levels of C-reactive protein were elevated in both infarcted and sham-operated animals whereas Troponin-I was elevated, and hearts were swollen, only after infarction. Conclusions: Contrast-enhanced MRI can be used to quantify infarct size and follow macrophage infiltration over time, which could be useful for assessing the efficacy of anti-inflammatory treatments for heart failure. doi:10.1016/j.yjmcc.2006.03.017
003. Monitor of adipose-derived stem cells using magnetic resonance imaging B. Xiang, J. Deng, J. Wang, M. Gruwel, M. Jackson, R. Deslauriers, G. Tian. Institute for Biodiagnostics, National Research Council, Winnipeg, Manitoba, Canada The present study was to determine whether proliferation and concentration of the adipose-derived stem cells (ADSCs) could be assessed using MR imaging. ADSCs were isolated from the fat tissue in rats and pigs and then labeled with ferumoxide (50 Ag/ml). The labeled ADSCs were continuously cultured for three more weeks. To assess the influence of cell proliferation on ADSC MR signal intensity, the labeled ADSCs were collected at different passages (1st to 6th) and embedded in a culture medium containing 0.1% agarose at a concentration of 2 106/ml. To assess dependence of ADSC MR signal intensity on cell concentration, the ADSCs were embedded in the same medium at six different concentrations, 2 106/ml, 1 106/ml, 5 105/ml, 2.5 105/ml, 1.25 105/ml, and 0.62 105/ml. We found that the ADSCs at different passages had very different MR T2 signal intensity. T2 relaxation times were linearly related to number of cell passage. Intracellular concentration of iron particles was found to be inversely dependent on cell passage. Moreover, we found that T2* relaxation times of the ADSCs were linearly related to cell concentration. The ADSCs injected into rat heart was readily detected in vivo as a signal void area on both T2- and T1weighted MR imaging at 1 week after cell injection. Our results suggest that proliferation and concentration of the ADSCs could be estimated in vivo using MR imaging in conjunction with ferumoxide. doi:10.1016/j.yjmcc.2006.03.018
001. Supra-normal (phospho-)creatine levels lead to heart failure in mice overexpressing the cardiac creatine transporter—a longitudinal study Michiel ten Hove, Darci Phillips, Julie Wallis, Craig A. Lygate, Alexandra Fischer, Liam Sebag-Montefiore, Dana Dawson, Karen Hulbert, Wen Zhang, Hugh Watkins, Kieran Clarke, Ju¨rgen E. Schneider, Stefan Neubauer. University of Oxford, UK In heart failure, myocardial creatine (Cr) levels are reduced due to reduced capacity of the myocardial creatine transporter (CrT), possibly contributing to contractile dysfunction. Increasing Cr levels therefore could be beneficial. Increased plasma levels in vivo, however, result in downregulation of the myocardial CrT. In order to increase myocardial Cr levels, we created a transgenic mouse overexpressing the myocardial CrT (CrT-OE). Compared to wild-type littermate controls (WT), myocardial creatine levels (HPLC) were increased in CrT-OE hearts (66 T 6 in WT vs. 133 T 52 nmol/mg protein in CrT-OE). Phosphocreatine (PCr) levels, measured by 31P MRS in isolated hearts, were also increased but to a lesser extent. Surprisingly, CrT-OE mice developed substantial LV dysfunction (3D-echo, MRI). Myocardial creatine content correlated closely with EF (r = 0.74, P = 0.0002), LVEDP (r = 0.52, P = 0.02) and dP/dtmax (r = 0.69, P = 0.0008). In spite of increased (P)Cr levels, CrTOE hearts showed increased [ADP]free and reduced free energy change for ATP hydrolysis. The accumulation of Cr and the development of heart failure were studied over time using in vivo 1H MRS and MRI to measure cardiac Cr and function, respectively. Mice were subjected to multiple measurements at 6 weeks, 4 months and 8 months of age, respectively. Results showed that the development of heart failure was preceded by the accumulation of creatine in the heart, being consistent with a causal relation. Overexpression of the cardiac CrT results in accumulation of myocardial Cr, followed by the development of heart failure. doi:10.1016/j.yjmcc.2006.03.016
002. Contrast-enhanced MRI tracking of post-infarct myocardial macrophage infiltration A.F. Catchpole, C.A. Carr, J.E. Schneider, D.J. Tyler, D.J. Stuckey, K. Clarke. Cardiac Metabolism Research Group, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford, UK Cardiac inflammation following an infarction may contribute to the development of heart failure. We aimed to track macrophage infiltration into the infarcted heart using noninvasive in vivo magnetic resonance imaging (MRI) knowing that blood monocytes endocytose superparamagnetic iron oxide particles (SPIOs), which create signal voids in the MR images. We postulated that the monocytes would home to infarct sites and differentiate into macrophages. Methods: Wistar rats were subjected to left coronary artery ligation. SPIOs (250 Amol Fe/kg bodyweight) were injected
921
after 1, 3 or 6 days. Macrophage infiltration was monitored by T2*-weighted MRI and ex vivo MR microscopy. C-reactive protein and Troponin-I were measured by ELISA. Results: Regions of hypointensity were detected in the damaged region of infarcted hearts in animals injected on days 3 and 6 and these were still visible at day 20. There were no signal voids observed in sham-operated animals or those injected with SPIOs on day 1, indicating that blood monocytes were not present for at least 24 h after infarction. Ejection fractions negatively correlated with the percentage of akinetic myocardium and signal void volumes. The presence of SPIOs in the myocardium was confirmed by MR microscopy. At 1– 2 days post-surgery, levels of C-reactive protein were elevated in both infarcted and sham-operated animals whereas Troponin-I was elevated, and hearts were swollen, only after infarction. Conclusions: Contrast-enhanced MRI can be used to quantify infarct size and follow macrophage infiltration over time, which could be useful for assessing the efficacy of anti-inflammatory treatments for heart failure. doi:10.1016/j.yjmcc.2006.03.017
003. Monitor of adipose-derived stem cells using magnetic resonance imaging B. Xiang, J. Deng, J. Wang, M. Gruwel, M. Jackson, R. Deslauriers, G. Tian. Institute for Biodiagnostics, National Research Council, Winnipeg, Manitoba, Canada The present study was to determine whether proliferation and concentration of the adipose-derived stem cells (ADSCs) could be assessed using MR imaging. ADSCs were isolated from the fat tissue in rats and pigs and then labeled with ferumoxide (50 Ag/ml). The labeled ADSCs were continuously cultured for three more weeks. To assess the influence of cell proliferation on ADSC MR signal intensity, the labeled ADSCs were collected at different passages (1st to 6th) and embedded in a culture medium containing 0.1% agarose at a concentration of 2 106/ml. To assess dependence of ADSC MR signal intensity on cell concentration, the ADSCs were embedded in the same medium at six different concentrations, 2 106/ml, 1 106/ml, 5 105/ml, 2.5 105/ml, 1.25 105/ml, and 0.62 105/ml. We found that the ADSCs at different passages had very different MR T2 signal intensity. T2 relaxation times were linearly related to number of cell passage. Intracellular concentration of iron particles was found to be inversely dependent on cell passage. Moreover, we found that T2* relaxation times of the ADSCs were linearly related to cell concentration. The ADSCs injected into rat heart was readily detected in vivo as a signal void area on both T2- and T1weighted MR imaging at 1 week after cell injection. Our results suggest that proliferation and concentration of the ADSCs could be estimated in vivo using MR imaging in conjunction with ferumoxide. doi:10.1016/j.yjmcc.2006.03.018