Assessing alterations in myocardial MN²⁺ fluxes following myocardial infarction in a murine model using T₁₋-mapping manganese-enhanced MRI

Abstract

During cardiac ischemia, intracellular calcium (Ca²⁺) overload occurs which can result in cell death. MRI T₁ shortening contrast agent manganese (Mn²⁺) acts as a surrogate marker for Ca²⁺. Cardiac T₁-mapping manganese-enhanced MRI (MEMRI) techniques were applied to study the efflux of Mn²⁺ from both healthy mice and mice post-myocardial infarction (MI) surgery. Temporal changes in the myocardial relaxation rate, ∆R₁, post-MnCl₂ infusion were shown to be linearly correlated to the absolute Mn content. The relative importance of individual efflux mechanisms in healthy mice was investigated by inhibiting the sodium-calcium exchanger (NCX) with SEA0400, following infusion of MnCl₂, with SEA0400 reducing the rate of Mn²⁺ efflux. Regional alterations in Mn²⁺ uptake and efflux were also studied post-myocardial infarction, allowing for the identification of potentially salvageable myocardium in the peri-infarcted zone surrounding the necrosed tissue. Application of pharmacokinetic models to in vivo and elemental analysis data from both the healthy and MI mice groups suggested that the NCX was more active in Mn²⁺ efflux than for Ca²⁺ and that there was an increase in Mn²⁺ uptake due to the disease condition, consistent with Ca²⁺ overloading. Studying Mn²⁺ efflux using these protocols could provide a pre-clinical model for examining alterations in relative Ca²⁺ fluxes and to potentially monitor disease progression.