Preliminary Experience with Intracellular Manganese Ions as Contrast Agents in the Human Myocardium

BACKGROUND: Animal experiments have shown that intracellular manganese (Mn) ions (Mn2+) may be promising contrast agents for imaging (MnMRI) of normal and ischemic myocardium. Cardiomyocytes accumulate paramagnetic Mn2+ by entry via slow calcium (Ca2+) channels and by transient trapping in mitochondria. Binding to intracellular proteins enhances relaxivity of Mn2+ strongly and improves further signal intensity in T1 weighted images. The aim of the present study was to examine whether MnMRI may be applied for imaging of human myocardium. METHOD: 3 groups (n=5) of human volunteers (20-29 years) received respectively 5, 10 and 15 micromol/kg of MnDPDP (Mn-dipyridoxyl-diphosphate) by 30 min infusion out-of-magnet. R1 was measured before and 30 min and 1, 2, 4, 8 and 24 hours following infusion. MR-examinations were performed at 1.5 T (Siemens Magnetom Symphony) with use of a thorax surface coil. R1 was measured in a single short-axis slice of left ventricular myocardium using an inversion recovery (IR) turbo-FLASH sequence with varying TI. Myocardial R1 in s-1 was calculated as the mean value from 16 sectors, and ΔR1 was calculated as the difference between control and postinfusion. RESULTS: No participant experienced adverse effects during infusion of MnDPDP. Myocardial R1 rose from 0.96 s-1 to 1.35 s-1, and was parallelled by a marked enhancement of signal intensity and an improved demarcation of the left ventricular wall. Mean control R1 was 0.98 s-1 (SD=0.02 s-1). Individual ΔR1 values varied between 0.33 and 0.45 s-1. As indicated in Figure 2, ΔR1 values (s-1) after 1-2 hours were 0.36 (SD=0.02), 0.43 (SD=0.03), and 0.43 (SD=0.01) in the three groups. There was a tendency to higher ΔR1 with an increase in dose from 5 to 10 micromol/kg, but not from 10 to 15 micromol/kg. R1 remained elevated before slowly declining after 2 hours. Still after 24 hours R1 was higher than control. R1 analysis from intraventricular blood revealed a control value of 0.65 s-1 and a mean value 1 hour postinfusion of 0.68 s-1. DISCUSSION: A main result was the first time documentation that MnMRI may be applied to imaging of the human myocardium. Thus a close to 45 % rise in R1 and an imaging window of 2-4 hours were observed. However promising, kinetics and dynamics of MnMRI are complex with many factors to consider and exploit. Among these are: the formulation of contrast media for Mn2+ release; the dose and duration of infusion or injection; plasma protein binding and low extracellular Mn2+; the major uptake of protein-bound Mn2+ in liver; the influence of sympathetic tone; and finally, the more exquisite uptake of Mn2+ in cardiomyocytes and other excitable cells. As shown in the present study, a 30 min infusion of the preferably slow Mn2+ releaser MnDPDP raised R1 effectively, but an apparent saturation occurred when the dose was raised above 5-10 micromol/kg. Whether the documented rise in R1 can be further enhanced with MnDPDP or with other Mn2+ releasers remains to be seen.