Applications of manganese‐enhanced magnetic resonance imaging (MEMRI) to imaging of the heart

Abstract

The use of manganese-based MRI contrast materials, either manganese salts or chelates, has spanned the entire timeframe of cardiac MRI. However interest in Mn compounds for cardiac MRI has been sporadic because of concerns over cardiotoxicity associated with significant concentration of free Mn 2þ and notable success of gadolinium chelates in cardiac application. Initial strategies to overcome cardiotoxicity included chelation of Mn 2þ to reduce the concentration of the free ion in vivo, and addition of Ca 2þ in combination with Mn 2þ to competitively reduce binding of Mn 2þ to Ca 2þ channels in the heart. Both approaches met with mixed success, but were subsequently discontinued in favor of gadolinium-based approaches. However Mn 2þ -based media potentially offer unique advantages for characterizing heart pathology over conventional Gd-based contrast media because Mn 2þ is taken up by heart cells and retained for hours. Cellular uptake occurs through calcium channels so contrast on delayed images may be interpreted according to regional or global functional status. Since Mn 2þ is retained in the heart, Mn-based media can be administered outside the magnet and the contrast pattern measured hours later to provide assessment of uptake. A key issue is whether sufficient accumulation of Mn 2þ in heart cells for imaging can occur without cardiotoxicity, and findings to date indicate this is possible. This review examines the current status of Mn 2þ -enhanced MRI of heart with particular focus on the hypothesis that Mn 2þ uptake can be interpreted in terms of heart function. Copyright # 2004 John Wiley & Sons, Ltd.KEYWORDS: magnetic resonance imaging; manganese; contrast media; myocardial ischemia; myocardial function; myocardial perfusion OVERVIEW Manganese (II) was the first MRI contrast agent. Lauterbur et al. 1 found that administration of inorganic salts of divalent Mn increased R 1 , particularly in liver, kidney, and heart. 2 In the heart increased R 1 of tissue was proportional to quantity of Mn 2þ accumulated within it, 1,2 and both quantity of Mn 2þ and R 1 enhancement were reduced in myocardium distal to an occluded artery. Mn 2þ was considered a promising contrast material for use in cardiac MRI because of its potent R 1 enhancement, its fairly rapid uptake by heart cells and its only moderate toxicity. Manganese is an essential trace mineral with a stable physiologic pool and a physiological system for handling it. Most notably, manganese is essential to aerobic organisms because Mn 2þ is required by mitochondrial superoxide dismutase (SOD). 3 The important issue was the moderate toxicity. In addition to manganese poisoning, which caused parkinsonism-like symptoms after chronic overexposure, Mn 2þ was known to block normal calcium fluxes in the heart, which caused a prominent cardiotoxicity. A dose of 0.1 mmol/kg administered by rapid intravenous injection kills rats, 2 stopping the heart within a few minutes. After a few early encouraging MRI studies with low doses of MnCl 2 , 2,4,5 Wolf and Ba...

KATP channel knockout worsens myocardial calcium stress load in vivo and impairs recovery in stunned heart

“…The divalent manganese ion is a recognized indicator of Ca 2ϩ influx, as Mn 2ϩ enters cells through voltage-gated Ca 2ϩ channels (41). Mn 2ϩ is also paramagnetic, resulting in shortening of the spin-lattice relaxation time constant T1, which yields positive contrast enhancement in T1-weighted MRI, specific to tissues in which the ion has accumulated (19,55). Manganeseenhanced MRI, applied in the present study, combines these properties to trace in an MRI-detectable manner regions of Ca 2ϩ uptake.…”

Characterization of cryoinjury-induced infarction with manganese-and gadolinium-enhanced MRI and optical spectroscopy in pig hearts

“…Magnetic resonance imaging (MRI) including contrast-enhanced MRI is a valuable tool for assessment of progression of cardiac infarction [37], [38], [39], [40], [41], [42], [43], [44] and [45]. Commonly used T 1 -type contrast agents include gadolinium (Gd 3+ ) and manganese (Mn 2+ ) chelates [42].…”

“…In contrast, Mn 2+ is an intracellular-type contrast agent, which enhances viable tissue visibility [42] and [45]. In the excitable tissues such as heart and brain, the major route for Mn 2+ entry is via plasmalemmal voltage-gated Ca 2+ channels owing to the similarity of biochemical properties of Ca 2+ and Mn 2+ and limited ion-selectivity of these channels [46] and [47].…”

“…In the excitable tissues such as heart and brain, the major route for Mn 2+ entry is via plasmalemmal voltage-gated Ca 2+ channels owing to the similarity of biochemical properties of Ca 2+ and Mn 2+ and limited ion-selectivity of these channels [46] and [47]. Normal cardiomyocytes can retain Mn 2+ for hours due to inability of Ca 2+ efflux transporters to extrude it and its subsequent uptake by mitochondria [45] and [48]. Our recent study indicated that Mn 2+ could highlight ischemic areas due to impaired perfusion, while in the chronically infarcted areas, in which perfusion was partially reestablished by host repairing processes, significantly enlarged extracellular volume becomes the major determinant governing the equilibrium contrast distribution [5].…”

The role of imaging and molecular imaging in the early detection of metabolic and cardiovascular dysfunctions

“…69,[72][73][74] The discovery that cardiotoxicity was mainly due to extracellular Mn 2 þ instead of intracellular Mn 2 þ and that the slow infusion of a low, non-toxic concentration of Mn 2 þ leads to high tissue accumulation prompts reuse of Mn-based contrast media for cardiac imaging. 75 Mn-enhanced cardiac MRI was then re-evaluated, particularly in the context of Mn 2 þ being a surrogate of Ca 2 þ uptake by cardiomyocytes. Recent studies obtained promising results in differentiating viable from non-viable segments in showing different enhancement.…”