Remote regions showed larger increases in R(1) than infarcted regions. This is most likely due to selective and slow Mn accumulation in viable myocytes.
Purpose:To assess magnitude and duration of changes in myocardial longitudinal relaxation rate (R 1 ) in humans following infusion of the manganese (Mn) releasing contrast agent MnDPDP (Mn-dipyridoxyl-diphosphate). Materials and Methods:Fifteen healthy volunteers were divided into three groups. After initial myocardial and liver R 1 measurements using an inversion recovery (IR) turbo fast low-angle shot (FLASH) sequence at 1.5 Tesla, the groups were given different doses of intravenous MnDPDP: 5, 10 and 15 mol/kg body weight, respectively, over 30 minutes. R 1 measurements were then repeated at 1, 2, 4, 8, and 24 hours after the infusion ended. Results:The left ventricular wall R 1 prevalue was 0.98 second -1 (Ϯ0.04). R 1 increased on average (all 15 subjects) 0.41 second -1 (Ϯ0.09). The increase was present one hour after the end of the infusion, remained relatively constant the next two hours, and then declined gradually. After 24 hours, there was still a moderate R 1 elevation present, with an average R 1 -value of 1.16 (Ϯ0.05). There were only small differences in myocardial R 1 responses between the three doses investigated, which was contrasted by a marked dose-response in liver tissue. Conclusion:MnDPDP gave a significant and prolonged rise in myocardial R 1 even at a dose of 5 mol/kg. The R 1 -values in the myocardium did not increase linearly with higher doses. THE USE OF manganese-containing contrast agents in magnetic resonance imaging (MRI) for the study of the myocardium has been debated for several years. The background for this interest in manganese is that myocardial cells actively accumulate manganese ions (Mn 2ϩ ) through voltage-dependent slow calcium channels in the cell membrane (1-4). This has raised the question of whether intracellular manganese can be used as a contrast agent for MRI-based myocardial viability diagnosis.Thus far, several research groups have studied myocardial effects of manganese in MRI. Early studies showed that manganese contrast could be used to demarcate infarcted regions in animal hearts, first in excised hearts (5,6), and later on in images obtained with live animals (7-9). The accumulated manganese led to markedly increased longitudinal relaxation rates (R 1 ) in normal myocardium (3,8 -11). Theoretically, the relationship between the concentration of contrast agent in a tissue and the corresponding R 1 should be close to linear. Southon et al (11) demonstrated a steady increase in myocardial R 1 in pigs with intravenous doses of manganese dipyridoxyl diphosphate (MnDPDP) up to 20 mol/kg. Both Bremerich et al (8) and Wendland et al (9) found that R 1 -values increased with increasing doses of MnDPDP in rat myocardium. Both studies used doses of 25, 50, and 100 mol/kg, given over 1.5 and 3 minutes, respectively. Both showed an initial higher rise in R 1 in infarcted myocardium 5-10 minutes after the infusions than in normal myocardium. However, these initial high R 1 -values in infarcted myocardium decreased with time, while normal myocardium had a steady increa...
Purpose: To develop an in vivo MR method for evaluation of myocardial calcium channel activity through quantification of apparent unidirectional manganese influx constants following manganese dipyridoxyl-diphosphate (MnDPDP) infusions. Materials and Methods:A total of 10 healthy volunteers were divided in two groups, and received 5 mol of MnD-PDP per kg of body weight intravenously in a 1.5 Tesla scanner over five or 30 minutes, respectively. A fast inversion recovery gradient echo sequence was used to estimate pre-and postcontrast R 1 values and to measure signal changes following infusions. By assuming equal longitudinal relaxivity (r 1 ) of the contrast in all tissue compartments, signal changes in blood and myocardial tissue yielded temporal input and tissue contrast concentrations respectively. Through a two-tissue compartment model, apparent unidirectional influx constants (K i ) for myocardial manganese accumulation were estimated.Results: Consistent values for K i in left ventricular wall were found, with a mean value of 5.96 mL/100 g/minute (SD ϭ 0.49; N ϭ 10). No statistical significant differences in K i were found between the two infusion groups. Conclusion:Since unidirectional manganese accumulation depends upon intact myocyte membranes with functioning calcium channels, the use of unidirectional manganese influx rates may be a valuable research tool for in vivo studies of myocyte functioning in myocardial disease.
The semistable chelate manganese (Mn) dipyridoxyl diphosphate (MnDPDP, mangafodipir), previously used as an intravenous (i.v.) contrast agent (Teslascan™, GE Healthcare) for Mn-ion-enhanced MRI (MEMRI), should be reappraised for clinical use but now as a diagnostic drug with cytoprotective properties. Approved for imaging of the liver and pancreas, MnDPDP enhances contrast also in other targets such as the heart, kidney, glandular tissue, and potentially retina and brain. Transmetallation releases paramagnetic Mn2+ for cellular uptake in competition with calcium (Ca2+), and intracellular (IC) macromolecular Mn2+ adducts lower myocardial T1 to midway between native values and values obtained with gadolinium (Gd3+). What is essential is that T1 mapping and, to a lesser degree, T1 weighted imaging enable quantification of viability at a cellular or even molecular level. IC Mn2+ retention for hours provides delayed imaging as another advantage. Examples in humans include quantitative imaging of cardiomyocyte remodeling and of Ca2+ channel activity, capabilities beyond the scope of Gd3+ based or native MRI. In addition, MnDPDP and the metabolite Mn dipyridoxyl diethyl-diamine (MnPLED) act as catalytic antioxidants enabling prevention and treatment of oxidative stress caused by tissue injury and inflammation. Tested applications in humans include protection of normal cells during chemotherapy of cancer and, potentially, of ischemic tissues during reperfusion. Theragnostic use combining therapy with delayed imaging remains to be explored. This review updates MnDPDP and its clinical potential with emphasis on the working mode of an exquisite chelate in the diagnosis of heart disease and in the treatment of oxidative stress.
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