LAUSR

Introduction Manganese is a calcium analogue and potent T1-contrast agent for MRI that enters cardiomyocytes through active calcium channels, thus reducing T1 in viable myocardium.1 We hypothesized that T1-mapping-MRI could measure Mn levels in the myocardium acutely after myocardial infarction (MI) allowing quantification of intracellular Ca response to ischemic injury. Methods Mice received intraperitoneal injections of 0.10 mmol/kg MnCl240 min before MI. T1-mapping-MRI was performed at 1, 2 and 3 hours and 2 days after MI. R1 values (1/T1=the relaxivity of the tissue) were analysed from the area-at-risk of infarction segments (AAR-MI, n=12) and viable segments (Viable-MI, n=12) of infarcted hearts, and naïve control heart (Viable-Naïve, n=12). Imaging was performed using a 9.4T Agilent MRI system and a multi inversion time Look-Locker sequence in the short-axis orientation (TE/TR=3.04/1.11 ms, 18 inversion times at consecutive R waves, 100 excitation pulse, slice thickness=1.0 mm, FOV=25.6 × 25.6 mm, matrix size=128 × 128) as described.2 Results As soon as 1 hour after MI, R1 values increased in Viable-MI tissue compared with AAR-MI (p<0.0001) and naïve controls. R1 values continued to rise in the Viable-MI at 2 and 3 hours (p=0.02, p=0.01. Figure 1 and 2). When the same animals were imaged 2 days post-MI, R1 values were still significantly higher in the Viable-MI tissue compared with AAR-MI tissue (p=0.03). However, Viable-MI tissue had similar R1 to naïve hearts, while R1 in the infarcted AAR-MI was lower than of the naïve myocardium (p=0.03. Figure 1 and 2).Abstract 4 Figure 1 T1 Maps of Mn uptake in acute myocardial infarctionT1 Maps acquired at 1,2,3 and 28 h after coronary occlusion (top) or in naïve mouse hearts (bottom). In the first hours after MI, T1 in viable segments of infracted hearts was decreased compared with the area at risk of MI and the naïve myocardium owing to increased Mn uptake. By 48 h, T1 in the infarct was higher than viable segments owing to reduced Mn uptake in the non-contractile ischemic zoneAbstract 4 Figure 2 R1 values in acute myocardial infarction after Mn infusionR1 values in MI mouse hearts at 1, 2, 3 & 48 h after myocardial infarction and in naïve mouse hearts at the same time points after Mn infusion. Viable-MI = Remote myocardium at 1 to 3 hours after occlusion, AAR-MI = Area at risk at 1 to 3 hours after occlusion, Viable-Naïve = Remote myocardium in naïve control group Discussion Acutely after ischemic injury a large increase in R1 (reflecting increased Mn2+ uptake) occurred in Viable-MI myocytes, likely due to elevated catecholamine levels acutely post-MI; increased cardiac work and thus increased Ca2+/Mn2+ uptake. By 2 days the catecholamine storm has passed and R1 levels in the surviving myocardium normalise, while Mn uptake in the dead infarct region was reduced due to lack of functional myocytes. Conclusions T1-Mapping Manganese-enhanced-MRI offers a valuable in vivo tool for optimisation of the many emerging pharmacological and biological interventions which aim to modulate Ca2+ homeostasis acuity after MI. References . Waghorn B, Edwards T, Yang Y, Chuang K-H, Yanasak N, Hu TC-C. Monitoring dynamic alterations in calcium homeostasis by T1-weighted and T1-mapping cardiac manganese-enhanced MRI in a murine myocardial infarction model. NMR in Biomedicine2008;1102–1111. . Stuckey DJ, McSweeney SJ, Thin MZ, Habib J, Price AN, Fiedler LR, … Schneider MD. T1 mapping detects pharmacological retardation of diffuse cardiac fibrosis in mouse pressure-overload hypertrophy. Circulation: Cardiovascular Imaging2014;7:240–249.