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

Abstract

Manganese has been used as a T(1)-weighted MRI contrast agent in a variety of applications. Because manganese ions (Mn(2+)) enter viable myocardial cells via voltage-gated Ca(2+) channels, manganese-enhanced MRI is sensitive to the viability and inotropic state of the heart. In spite of the established importance of Ca(2+) regulation in the heart both before and after myocardial injury, monitoring strategies to assess Ca(2+) homeostasis in affected cardiac tissues are limited. This study implements a T(1)-mapping method to obtain quantitative information both dynamically and over a range of MnCl(2) infusion doses. To optimize the current Mn(2+) infusion protocols, we performed both dose-dependent and temporal washout studies. A non-linear relationship between infused MnCl(2) solution dose and increase in left ventricular wall relaxation rate (DeltaR(1)) was observed. Control mice also exhibited significant Mn(2+) clearance over time, with a decrease in DeltaR(1) of approximately 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 Mn(2+) dose, DeltaR(1), 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 Ca(2+) handling in vivo because of the physiological remodeling after myocardial infarction. Left ventricular free wall DeltaR(1) 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.

Myocardial infarction quantification with Manganese‐Enhanced MRI (MEMRI) in mice using a 3T clinical scanner

“…All of these studies used a model of permanent coronary occlusion. In this mouse model, infarct size determined by TTC at 7 days was linearly correlated to the infarct size measured from MEMRI (13) but a lower signal intensity, suggesting a decreased Mn 2þ accumulation was also observed in the peri-infarct area where ischemic tissue may also be present (5). The type of coronary occlusion model, as well as the timing of examination after the induction of the myocardial injury, may also impact MEMRI experiments.…”

“…The presence of dobutamine (which is known to increase Ca 2þ influx into the heart) during Mn 2þ infusion increases signal enhancement in T1-weighted images whereas the calcium channel blocker diltiazem reduces it (7). A reduced Mn 2þ accumulation has also been observed in stunned cardiomyocytes (8) as well as in the zone adjacent to a myocardial infarct (5). Manganese-Enhanced MRI (MEMRI) has also been used to assess myocardial infarction in various animal models from pig to rat (9)(10)(11)(12).…”

“…However, even if this method has largely proven its efficiency, it has some disadvantages over Mn 2þ late enhancement. First, the time window during which assessment is possible is relatively short with Gd 3þ [around 1 h (25)] compared with Mn 2þ where ions can stay in mitochondria for several hours (5). Also, performing infarct quantification too early with Gd 3þ can lead to an overestimation of the infarct zone that restrains again this time window between 20 and 60 min after injection (25)(26)(27).…”

“…Manganese-Enhanced MRI (MEMRI) has also been used to assess myocardial infarction in various animal models from pig to rat (9)(10)(11)(12). Only a few studies, however, investigated the possible use of MEMRI for myocardial infarction assessment in mice (5,13). All of these studies used a model of permanent coronary occlusion.…”

“…Manganese ion (Mn 2þ ) was quickly recognized as an efficient intracellular MR contrast agent as it enters excitable cells via L-Type voltage dependant channels to accumulate in mitochondria and also induces a strong T1 shortening effect (4). As an analog of the Calcium ion (Ca 2þ ), Mn 2þ can assess Ca 2þ homeostasis in-vivo generating an important interest for researchers (5). In fact, Ca 2þ cycling is of vital importance to cardiac cell function and plays an important role in ventricular dysfunction such as heart failure (6).…”