Monitoring dynamic alterations in calcium homeostasis by T₁-weighted and T₁-mapping cardiac manganese-enhanced MRI in a murine myocardial infarction model

Manganese has been used as a T₁-weighted MRI contrast agent in a variety of applications. Because manganese ions (Mn²⁺) enter viable myocardial cells via voltage-gated Ca²⁺ channels, manganese-enhanced MRI is sensitive to the viability and inotropic state of the heart. In spite of the established importance of Ca²⁺ regulation in the heart both before and after myocardial injury, monitoring strategies to assess Ca²⁺ homeostasis in affected cardiac tissues are limited. This study implements a T₁-mapping method to obtain quantitative information both dynamically and over a range of MnCl₂ infusion doses. To optimize the current Mn²⁺ infusion protocols, we performed both dose-dependent and temporal washout studies. A non-linear relationship between infused MnCl₂ solution dose and increase in left ventricular wall relaxation rate (DR₁) was observed. Control mice also exhibited significant Mn²⁺ clearance over time, with a decrease in DR₁ of ~50% occurring in just 2.5 h. The complicated efflux time dependence possibly suggests multiple efflux mechanisms. With the use of the measured relationship between infused Mn²⁺ dose, DR₁, and inductively coupled plasma mass spectrometry data analysis provided a means of estimating the absolute heart Mn concentration in vivo. We show that this technique has the sensitivity to observe or monitor potential alterations in Ca²⁺ handling in vivo because of the physiological remodeling after myocardial infarction. Left ventricular free wall DR₁ values were significantly lower (P = 0.005) in the adjacent zone, surrounding the injured myocardial tissue, than in healthy tissue. This inferred reduction in Mn concentration can be used to estimate potentially salvageable myocardium in vivo for future treatment or evaluation of disease progression.