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(Radiology. 2000;216:524-530.)
© RSNA, 2000

Experimental Studies

Normal and Infarcted Myocardium: Differentiation with Cellular Uptake of Manganese at MR Imaging in a Rat Model1

Jens Bremerich, MD, Maythem Saeed, DVM, PhD, Håkan Arheden, MD, PhD, Charles B. Higgins, MD and Michael F. Wendland, PhD

1 From the Department of Radiology, University of California, 505 Parnassus Ave, San Francisco, CA 94143-0628. Received March 3, 1999; revision requested April 27; revision received October 28; accepted November 2. Supported in part by a research grant from Nycomed Amersham Imaging, Oslo, Norway. J.B. supported by the ADUMED Foundation, Gentilino, Switzerland. Address correspondence to M.F.W. (e-mail: mike.wendland@radiology.ucsf.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To assess whether normal myocardium can be distinguished from infarction at magnetic resonance (MR) imaging with low doses of manganese dipyridoxyl diphosphate (Mn-DPDP).

MATERIALS AND METHODS: After 1-hour coronary arterial occlusion and 2-hour reperfusion, three groups of eight rats each were injected with 25, 50, or 100 µmol of Mn-DPDP per kilogram of body weight. The longitudinal relaxation rate (R1) in normal myocardium, reperfused infarction, and blood was repeatedly measured at inversion-recovery echo-planar imaging before and for 1 hour after the administration of contrast material. Afterward, several animals from each group were examined at high-spatial-resolution inversion-recovery spin-echo (SE) MR imaging.

RESULTS: Manganese accumulated in normal myocardium but was cleared from reperfused infarction and blood. One hour after the administration of Mn-DPDP, R1 in normal myocardium (1.53 sec-1 ± 0.03, 1.73 sec-1 ± 0.03, and 1.94 sec-1 ± 0.02, respectively, for 25, 50, and 100 µmol/kg) was significantly (P < .05) faster than that of reperfused infarction (0.99 sec-1 ± 0.03, 1.11 sec-1 ± 0.03, and 1.48 sec-1 ± 0.06). Normal myocardium appeared hyperintense on T1-weighted inversion-recovery SE MR images and was clearly distinguishable from reperfused infarction.

CONCLUSION: Mn-DPDP–enhanced inversion-recovery echo-planar and SE MR images demonstrated retention of manganese in normal myocardium and clearance of manganese from infarction. Mn-DPDP has characteristics similar to those of widely used thallium and may be useful in the assessment of myocardial viability at MR imaging.

Index terms: Animals • Magnetic resonance (MR), contrast enhancement, 511.12143 • Magnetic resonance (MR), echo planar, 511.121416 • Magnetic resonance (MR), inversion recovery, 511.121413 • Manganese • Myocardium, infarction, 511.771 • Myocardium, MR, 511.121411, 511.121413, 511.121415, 511.121416, 511.12143, 511.12146


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
The noninvasive assessment of myocardial viability has proved to be useful in the identification of myocardium that will benefit from coronary revascularization. Evidence of myocardial viability usually relies on the scintigraphic demonstration of uptake of various metabolic tracers, such as thallium (1–3), 2-[fluorine 18]fluoro-2-deoxy-D-glucose, and carbon 11–labeled fatty acids or acetate (4,5), or on the demonstration of contractile reserve in a dysfunctional region (6,7).

Manganese 52m radionuclide has also been considered to be promising for use at cardiac scintigraphic tomography (8–10). Mn2+ cation is an essential trace metal that is rapidly taken up by myocytes through voltage-operated calcium channels and that accumulates in mitochondria (11), where it is a necessary cofactor of mitochondrial superoxide dismutase. Its uptake and distributional properties in the heart have been compared with those of thallium, which is taken up by myocytes through potassium channels. Chauncey et al (8) demonstrated a high myocardium-to-blood ratio for 54Mn that exceeded that of 201Tl and persisted for hours. Atkins et al (9) reported a short plasma half-life (<1 minute in dogs) for 54Mn ions and obtained 52mMn positron emission tomograms on which tracer uptake was proportional to blood flow in dog hearts with regional occlusion.

Manganese has also been used in contrast material–enhanced magnetic resonance (MR) imaging of the heart. Mn2+ was explored initially (12–17), and the cation was shown to provide substantial enhancement of myocardium on T1-weighted images; its early distribution was linearly related to regional blood flow. More recently, it was reported that the Mn2+ cation is rapidly cleared from reperfused infarcted myocardium but not from noninfarcted regions (18). But enthusiasm for Mn2+-enhanced MR imaging has been tempered by the cardiotoxic effects of the ion resulting from competitive calcium antagonism with effective doses at MR imaging (16) and a low median lethal dose in rodents (19). Several manganese chelate formulations have also been studied (20–22). Recently, manganese dipyridoxyl diphosphate (Mn-DPDP) was approved for clinical hepatic imaging at a dose of 5 µmol per kilogram of body weight (23,24).

Mn-DPDP is distributed throughout the extracellular space and is cleared from the blood by means of hepatic elimination (25). After intravenous administration, Mn-DPDP is metabolized by means of dephosphorylation and is transmetallated with zinc, resulting in the release of Mn2+ from the ligand (26–28). Since intact Mn-DPDP and dissociated Mn2+ have distinct distributional and kinetic properties, after the administration of Mn-DPDP, it may be possible to obtain MR images on which contrast enhancement is primarily provided by the dissociated Mn2+ ions that have accumulated in viable myocytes. If so, the contrast enhancement would be relatable to the regional functional activity or viability of the myocardial cells in a manner analogous to that of delayed 201Tl imaging.

Earlier MR imaging of the heart included the use of a very high dose of Mn-DPDP, 400 µmol/kg (21,22), compared with that approved for clinical use. Most of the contrast enhancement in the heart provided by this material was thought to have been caused by the chelated extracellular fraction of manganese. The extent to which myocardial cellular uptake of dissociated Mn2+ may have contributed to enhancement is not known.

Accordingly, the purpose of this study was to determine whether normal myocardium can be distinguished from infarction at enhanced MR imaging with low doses of Mn-DPDP. Specifically, we wanted to determine (a) if and when contrast enhancement in the myocardium is dominated by myocardial uptake of dissociated Mn2+ ions after the administration of Mn-DPDP and (b) whether contrast enhancement provided by myocardial Mn2+ uptake is detectable on MR images when the administered dose of Mn-DPDP approaches the clinically approved dose in hepatobiliary applications.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
MR Contrast Media
The synthesis and characterization of Mn-DPDP has been described (29,30). This agent is distributed throughout the extracellular space in the heart as long as it remains intact. In the liver, manganese is separated from the ligand and is taken up by hepatocytes; the ligand is mostly cleared by the kidney (26). Mn-DPDP has a plasma half-life of approximately 15 minutes (25,26). The agent was obtained as the clinical formulation containing 10 mmol/L Mn-DPDP (Teslascan [mangafodipir trisodium]; Nycomed Amersham Imaging, Oslo, Norway).

Animal Preparation
Care and maintenance of experimental animals were performed in strict accordance with the National Institutes of Health (NIH) guidelines. The experimental protocol received prior approval from the committee on animal research at our institution. Female Sprague-Dawley rats (n = 24; 270–320 g body weight; Simonsen Labs, Gilroy, Calif) were anesthetized with sodium pentobarbital (Nembutal, Abbott Laboratories, North Chicago, Ill; 50 mg/kg; intraperitoneal injection). The chest was opened, and the anterior branch of the left coronary artery was occluded for 1 hour and reperfused for 2 hours to produce a reperfused myocardial infarction (31,32). This rat model of 1-hour ischemia followed by reperfusion produced an essentially complete infarction in the area at risk. There was minimal enlargement of the infarction with occlusion of longer duration (33).

Eight animals each received 25, 50, or 100 µmol/kg Mn-DPDP over 1.5 minutes by means of intravenous infusion via a catheter placed into a tail vein. The highest dose of contrast agent was chosen on the basis of findings from a pilot study that showed that retention of manganese in normal myocardium could be measured as the change in R1 ({Delta}R1) persistence.

MR Imaging Experiments
MR imaging was conducted with an Omega CSI 2-T system (Bruker Instruments, Fremont, Calif). Each animal was placed in a supine position in a home-built birdcage resonator and was connected to an electrocardiographic monitor that provided a trigger signal at the R wave for cardiac gating of the MR imaging sequences. The animal's core temperature was maintained at 37°C ± 1°C by using a recirculating heated water pad. A phantom with a known T1 value was placed beside the animal in the field of view.

Inversion-recovery echo-planar imaging was performed to measure the time course of {Delta}R1 in the left ventricular chamber blood, in normally perfused myocardium, and in reperfused infarcted myocardium, as described previously (34). Inversion-recovery echo-planar sequence parameters were the following: matrix, 64 x 64; field of view, 50 x 50 mm; section thickness, 2 mm; acquisition time, 32.7 msec; and 8,000/10 (repetition time msec/echo time msec), fully relaxed. For each R1 measurement, we acquired a set of 20 images on which the inversion time (TI) was incremented from 20 to 1,000 msec. R1 values were measured before the administration of Mn-DPDP and at 5-minute intervals during the 1st hour afterward.

After the R1 measurements were completed, several animals from each group were examined at conventional transverse T1-weighted ({approx}300/12) and partially saturated (ie, not fully relaxed) inversion-recovery spin-echo (SE) imaging to determine the feasibility of obtaining high-spatial-resolution images with contrast enhancement provided by differential myocardial Mn2+ uptake. The inversion-recovery sequence was used because it is more sensitive to contrast enhancement than the T1-weighted sequence. However, fully relaxed inversion-recovery images involve lengthy image acquisition times, and the postischemic region is conspicuous before the addition of contrast material.

Partial saturation established with a repetition time of less than or equal to 1,300 msec reduced the image acquisition time to approximately 10 minutes (for four signals acquired) and substantially reduced the signal intensity (SI) difference between postischemic and normal myocardium on precontrast images. This allowed depiction of Mn2+ uptake in a single postcontrast image, an important consideration when imaging is delayed after the administration of contrast material.

A nonselective radio-frequency pulse was used for spin inversion and was followed by an SE imaging sequence with the following parameters: 900–1,200/12/400–600 (repetition time msec/echo time msec/TI msec); raw data matrix, 256 x 128 zero-filled to 256 x 256; number of signals acquired, four; and image acquisition time, 10.2 minutes. All images were acquired at the midventricular level.

After the measurements were obtained at MR imaging, the animals were sacrificed by means of lethal injection of a 4 mol/L potassium chloride solution. The hearts were excised, rinsed, and cut by hand from apex to base in 2–3-mm-thick slices. The slices were stained by soaking them in a 2% solution of triphenyltetrazolium chloride at 37°C for 10 minutes. They were inspected for the presence of infarction. This staining procedure colors the normal myocardium brick red, whereas infarcted myocardium is unstained (35). The purpose of this staining procedure was to ensure that the preparation actually produced the infarction and that the approximate location and extent of the infarcted region were consistent with the lesion evident on MR images.

MR Imaging Data Analysis
Inversion-recovery echo-planar images were analyzed on a Macintosh computer (Apple Computer, Cupertino, Calif) by using a program in the public domain, NIH Image (NIH, Bethesda, Md; available at http://rsb.info.nih.gov/nih-image/). TI with null SI, or TInull, was determined for normal myocardium, reperfused infarcted myocardium, and ventricular blood (34). R1 (1/T1) values were calculated as follows: R1 = (ln 2)/TInull. {Delta}R1 was calculated as follows: {Delta}R1 = R1postcontrast - R1precontrast .

SE images were analyzed by measuring the SIs in the regions of interest within normal myocardium (septum), infarcted myocardium (anterolateral wall of the left ventricle), and background. From these values, SI ratios (SIinfarct/SInormal) and contrast-to-noise ratios (CNRs) (CNR = |SInormal - SIinfarct|/noise) were calculated.

Statistical Analysis
Statistical analysis was performed by using commercially available software (Statview v4.0 and SuperAnova; SAS Institute, Cary, NC). The effects of dose, region, and time on R1 values were evaluated by using a repeated measures analysis of variance (ANOVA) model with one between factor (dose) and two within factors (region and time). If the F ratio for effect was significant (P < .05), the individual mean differences for between factors were evaluated for significance by using a post hoc Scheffé test, and mean differences for within factors were evaluated by testing contrast values with a Greenhouse-Geisser degrees-of-freedom adjustment. All values are expressed as the mean ± SEM.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Demarcation of Infarcted Myocardium on SE Images
Infarcted myocardium was not distinguishable from normal myocardium before the administration of Mn-DPDP on either T1-weighted images (SI ratio = 0.97 ± 0.03, CNR = 0.50 ± 0.14, n = 8) or on partially saturated inversion-recovery SE images. With TI set to 500 msec, which prepared the myocardial SI to be slightly past the null point, the SI ratio for normal to infarcted regions (n = 3) was 0.80 ± 0.04, and the CNR was 0.65 ± 0.12 (Fig 1, A).



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  		Figure 1a. Representative transverse SE MR images obtained from rats with reperfused myocardial infarction. A, Midventricular inversion-recovery image (1,100/12/500) acquired before the administration of Mn-DPDP shows that the myocardial SI is low and has positive polarity. Inversion null was achieved at approximately 400 msec in the entire heart. The anterolateral wall (arrows) was infarcted, but the injured region was not defined. B, Inversion-recovery image (1,200/12/400) obtained 4 hours after the administration of 25 µmol/kg Mn-DPDP shows that the myocardial SI has positive polarity and the normal myocardium (arrows) is hyperintense compared with the infarcted myocardium. This finding signifies dissociated Mn2+ uptake and retention in normal myocardium and clearance from reperfused infarcted myocardium. LV = left ventricle. C, Conventional T1-weighted image (280/12) obtained immediately after the image in B in the same rat shows that the reperfused infarcted myocardium is not definable.

 


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  		Figure 1b. Representative transverse SE MR images obtained from rats with reperfused myocardial infarction. A, Midventricular inversion-recovery image (1,100/12/500) acquired before the administration of Mn-DPDP shows that the myocardial SI is low and has positive polarity. Inversion null was achieved at approximately 400 msec in the entire heart. The anterolateral wall (arrows) was infarcted, but the injured region was not defined. B, Inversion-recovery image (1,200/12/400) obtained 4 hours after the administration of 25 µmol/kg Mn-DPDP shows that the myocardial SI has positive polarity and the normal myocardium (arrows) is hyperintense compared with the infarcted myocardium. This finding signifies dissociated Mn2+ uptake and retention in normal myocardium and clearance from reperfused infarcted myocardium. LV = left ventricle. C, Conventional T1-weighted image (280/12) obtained immediately after the image in B in the same rat shows that the reperfused infarcted myocardium is not definable.

 


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  		Figure 1c. Representative transverse SE MR images obtained from rats with reperfused myocardial infarction. A, Midventricular inversion-recovery image (1,100/12/500) acquired before the administration of Mn-DPDP shows that the myocardial SI is low and has positive polarity. Inversion null was achieved at approximately 400 msec in the entire heart. The anterolateral wall (arrows) was infarcted, but the injured region was not defined. B, Inversion-recovery image (1,200/12/400) obtained 4 hours after the administration of 25 µmol/kg Mn-DPDP shows that the myocardial SI has positive polarity and the normal myocardium (arrows) is hyperintense compared with the infarcted myocardium. This finding signifies dissociated Mn2+ uptake and retention in normal myocardium and clearance from reperfused infarcted myocardium. LV = left ventricle. C, Conventional T1-weighted image (280/12) obtained immediately after the image in B in the same rat shows that the reperfused infarcted myocardium is not definable.

 
One hour after the administration of Mn-DPDP, the infarcted region was conspicuous on only inversion-recovery images. With TI set to 400 msec, the infarcted region was evident as a hypointense region when the Mn-DPDP dose was either 50 (SI ratio = 0.29 ± 0.04, CNR = 3.8 ± 0.7, n = 3) or 100 (SI ratio = 0.14 ± 0.03, CNR = 5.5 ± 0.8, n = 4) µmol/kg. But the infarcted myocardium was not well defined when the dose was 25 µmol/kg (SI ratio = 0.63 ± 0.11, CNR = 2.0 ± 0.4, n = 3).

However, conspicuity of the infarcted region was substantially improved at later times. In a separate group of four animals that received 25 µmol/kg Mn-DPDP and that were imaged 4 hours after the administration of contrast material, the infarcted region was highly conspicuous on inversion-recovery images (SI ratio = 0.34 ± 0.4, CNR = 4.5 ± 0.4) (Fig 1, B). The infarcted region was not evident on conventional T1-weighted SE images (SI ratio = 0.93 ± 0.04, CNR = 0.55 ± 0.10) (Fig 1, C). The infarcted zone demonstrated on Mn-DPDP–enhanced images was similar in location and extent to the region demarcated by means of triphenyltetrazolium chloride staining at postmortem examination.

Evolution of T1 after Mn-DPDP Administration
Before the administration of Mn-DPDP, mean R1 values did not significantly differ (P = .12) in the normal myocardium, infarcted myocardium, or chamber blood between dose groups (Table). But regional differences in mean R1 values were highly significant; in particular, R1 values were significantly greater in the normal myocardium than in infarcted myocardium (P < .001 on repeated measures analysis of variance [ANOVA] with precontrast measurements) (Table).


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  		Effect of Mn-DPDP Dose on Regional R1 Values
 
Injection of Mn-DPDP resulted in a dose-dependent increase in R1 values in all regions of interest. With all doses, normal myocardium (Fig 2, A) exhibited the smallest {Delta}R1 at 5 minutes after the injection, whereas reperfused infarction (Fig 2, B) exhibited the largest. Subsequently, {Delta}R1 in normal myocardium increased linearly with time in a manner consistent with uptake and retention of Mn2+, while {Delta}R1 in infarcted myocardium and left ventricular blood declined in a manner consistent with clearance of the contrast agent from these regions. The time course of clearance in both regions was well fitted with a biexponential, but not monoexponential, decay function. The initial half-life of {Delta}R1 in blood (Fig 2, C) was approximately 15 minutes.



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  		Figure 2. Graphs depict relaxation enhancement ({Delta}R1) in A, normal myocardium; B, reperfused infarction; and C, blood after the administration of 25, 50, or 100 µmol/kg Mn-DPDP. {Delta}R1 values linearly increased with time in normal myocardium, which is consistent with manganese accumulation and retention in intact myocardial cells. There is no slowing in manganese buildup in normal myocardium 1 hour after Mn-DPDP administration. {Delta}R1 values in the reperfused infarcted region and left ventricular blood decrease with time, which indicate clearance from these regions. Apparent clearance in blood and infarction is consistent with biexponential decay (fitted curves in respective graphs).

 
One hour after the administration of Mn-DPDP, the combination of increasing R1 values in normal myocardium and declining R1 values in infarcted myocardium resulted in a substantially greater R1 value in normal myocardium (Fig 3, Table). Consequently, the contrast enhancement patterns evident in the heart at 1 hour were dominated by the putative uptake and accumulation of Mn2+ in normal myocytes. Furthermore, the apparent uptake of Mn2+ by normal myocardium did not diminish during the initial hour after the administration of contrast material; this finding clearly suggests that further enhancement of the injury zone would occur at later times.



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  		Figure 3. Selected transverse inversion-recovery echo-planar images (8,000/10) of a rat heart subjected to 1-hour occlusion and 2-hour reperfusion were obtained 60 minutes after the administration of 100 µmol/kg Mn-DPDP. (Repetition time fluctuated slightly due to variations in the R-R interval.) TIs were as follows: A, 70 msec; B, 320 msec; C, 470 msec; and D, 570 msec. A, SI of the entire image has negative polarity. B, SI of the normal myocardium (arrows) passes through its null point. C and D, SI of reperfused infarction (arrowheads) and blood in the left ventricle (LV), respectively, traverse their null points.

 
It was for this reason that another group of four animals was prepared as described previously and imaged 4 hours after the administration of 25 µmol/kg Mn-DPDP. The R1 value of normal myocardium had increased substantially compared with the value observed at 60 minutes. The R1 value of blood had returned to precontrast values, and the R1 value of infarcted myocardium had recovered to within 15% of the values obtained before contrast enhancement (Table). In all cases, the measured R1 value of the phantom solution was within 5% of the true value (0.86 or 2.6 sec-1).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
The major findings of this study are the following: (a) After the administration of Mn-DPDP, {Delta}R1 increased over time in normal myocardium but declined in reperfused infarction and blood; this finding is consistent with Mn2+ uptake and retention in viable myocardium and Mn2+ clearance from nonviable myocardium. (b) The evolution of R1 enhancement after the administration of Mn-DPDP was slow, requiring up to 4 hours to reach maximal R1 increase in normal myocardium and complete clearance from the blood. (c) R1 enhancement provided by Mn2+ uptake, even at the lowest tested dose of 25 µmol/kg Mn-DPDP, was sufficient to enable discrimination between normal and infarcted regions at delayed MR imaging with a highly T1-sensitive pulse sequence. Moreover, our findings support the hypothesis that function-based contrast enhancement is obtained at delayed MR imaging after the administration of Mn-DPDP and suggest that myocardial viability may be assessed with this method.

When 25 µmol/kg MnCl2 was administered to rats that were subjected to reperfused infarction (18,36), {Delta}R1 of normal myocardium was maximal at 2.5 sec-1 ± 0.2 at 5 minutes and did not change substantially over 30 minutes. In reperfused infarcted myocardium, {Delta}R1 was also maximal at 2.5 sec-1 ± 0.3 at 5 minutes, which was followed by a rapid decline to 0.7 sec-1 ± 0.1 at 30 minutes; this finding was consistent with rapid redistribution in the infarcted region.

In the current study in which manganese was administered as the chelate Mn-DPDP, uptake of Mn2+ in normal myocardium was a much slower process and required more than 1 hour to achieve maximal {Delta}R1. This result is consistent with the concept that Mn-DPDP slowly releases Mn2+ (37), which, in turn, is rapidly taken up and retained by normal myocytes. In reperfused infarcted myocardium, maximal uptake of contrast agent occurred early after administration, and the agent was subsequently cleared. {Delta}R1 profiles obtained after the administration of Mn-DPDP were similar to those obtained with nonspecific agents such as gadopentetate dimeglumine in reperfused infarction (34); {Delta}R1 was greater in reperfused infarction than in blood, was maximal early after administration, and was cleared rapidly thereafter.

{Delta}R1 profiles observed in the normal myocardium (Fig 2, A) suggest a linear buildup of manganese in the normal myocardium. However, {Delta}R1 values at each time point have contributions from extracellular Mn-DPDP and from the intracellular dissociated Mn2+. Both change with time, but in opposite directions; {Delta}R1 arising from Mn-DPDP diminishes with time, whereas {Delta}R1 from intracellular manganese increases.

Furthermore, R1 relaxivity of the different complexes of manganese are not equivalent. Dissociated manganese has a higher relaxivity than that of Mn-DPDP. Dissociated manganese will form complexes with endogenous macromolecules in myocardial cells and plasma, and the relaxivity of these manganese complexes will again change.

It is entirely fortuitous that the summation of these processes results in a linear increase in {Delta}R1 in normal myocardium. Even given these complicated circumstances, one feature of the uptake rates in normal myocardium stands out. {Delta}R1 uptake curves are incompatible with a linear dose dependence. This can be appreciated most readily by examining the proportionality between {Delta}R1 values obtained at 60 minutes and the administered dose. After doses of 25, 50, or 100 µmol/kg Mn-DPDP were administered, the respective {Delta}R1 values at 60 minutes were 0.44 sec-1 ± 0.02, 0.61 sec-1 ± 0.03, or 0.81 sec-1 ± 0.04. Thus, when the dose was increased by two- and fourfold, the {Delta}R1 increased by only 1.39- and 1.84-fold.

This disproportionality may be related to the findings of Buck et al (10) who demonstrated that a fourfold increase in normal myocardium blood flow during dipyridamole stress produced only a 2.6-fold increase in 52mMn uptake in canine hearts. The lack of linearity between blood flow and tracer uptake led the authors to conclude that 52mMn positron emission tomography (PET) provides qualitative but not quantitative information about blood flow.

Previous MR Imaging Studies with Manganese
Manganese, in the form of MnCl2, was the first MR contrast agent used in the distinction of infarcted myocardium from normal myocardium (12). Intravenous administration of this agent increased T1 to a much greater extent in normal canine myocardium than in infarcted myocardium, in proportion to the quantity of retained Mn2+. In subsequent studies (13), the addition of MnCl2 enabled accurate measurement of infarction size and provided delineation of hypoperfused myocardium that matched 201Tl-defined defects on MR images of excised canine hearts (14).

Schaefer et al (17) found a linear relationship between regional microspheric blood flow and manganese concentration in canine hearts subjected to 5-minute coronary arterial occlusion and obtained in vivo images that depicted hypoperfused myocardium. In these studies, occlusive preparations were examined, images were acquired in the first few minutes when contrast distribution would have been more closely related to blood flow, and the Mn2+ was unchelated.

In prior Mn-DPDP–enhanced MR imaging studies of hearts (21,22), the dose of Mn-DPDP, 400 µmol/kg, was substantially greater than those used in the current study, and the nonspecific distribution properties of the chelated material were emphasized in contrast enhancement patterns. At that dose, Mn-DPDP was effective in the delineation of hypoperfused myocardium in animals with an occluded coronary artery (21) and was effective in the distinction of occlusive from reperfused myocardial infarction (22). In these studies, as in the previous studies in which MnCl2 was used, the territory of occluded vessels appeared hypointense on T1-weighted images. However, reperfused infarctions were evident as hyperintense regions during the 1st hour after Mn-DPDP administration because of the high dose used. In none of these previous studies was chelated Mn-DPDP or MnCl2 used to define nonviable myocardium on the basis of selective clearance of the contrast agent from necrotic myocardium.

Biodistribution of Manganese
Manganese retention in normal myocardium and clearance from infarcted myocardium are comparable to the features of widely used thallium. 201Tl has been used in the assessment of myocardial perfusion and viability with single photon emission computed tomography (1–3). Both manganese and thallium are characterized by high uptake in the heart. Chauncey et al (8) studied the uptake and myocardium-to-blood ratio of both 54Mn and 201Tl during 6 hours after intravenous administration. At hour after the administration of contrast material, ratios for 54Mn and 201Tl were similar (43.3 and 47.7, respectively [8]). But later, the myocardium-to-blood ratio of 54Mn markedly exceeded that of 201Tl. Four hours after injection, the ratios for 54Mn and 201Tl were 306.0 and 25.5, respectively (8). However, Buck et al (10) recently reported that 52mMn PET caused underestimation of blood flow at high flow values due to coronary vasodilation. They concluded that this agent is useful for qualitative but not quantitative depiction of blood flow on tomograms of the heart.

Unlike thallium, Mn2+ is taken up and released through the membranes of normal myocytes by means of different pathways. The predominant pathway for the influx of Mn2+ is the voltage-dependent Ca2+ channel (38,39). Ca2+ channel blockers such as nifedipine and verapamil hydrochloride attenuate the uptake of Mn2+ in normal myocardium (40). The pathways for the efflux of Mn2+ are not entirely understood. It is known, however, that influx occurs at a much faster rate than does efflux, resulting in protracted retention of Mn2+ in myocytes even after Mn2+ is cleared from the perfusate (38,39).

More recently, Brurok and co-workers (37,41,42,44) and Jynge and co-workers (43) reevaluated the cardiotoxic properties of MnCl2 compared with Mn-DPDP. Brurok et al (37,41,42) reported that manganese-induced reduction in myocardial performance is rapidly recovered when manganese is removed from the perfusate of Langendorf perfused rat hearts, even when the myocardium contained a concentration of manganese that was 60–70-fold greater than normal. Mn-DPDP was approximately one-tenth as potent as MnCl2 in the reduction of cardiac performance (41,43), whereas the quantity of manganese accumulated in myocardial cells during exposure to Mn-DPDP was approximately one-eighth of that accumulated during exposure to equimolar MnCl2 (42). Furthermore, Brurok et al (44) recently reported that Mn-DPDP and Mn2+ facilitate oxygen radical dismutation and could, in principle, act to protect the heart against oxygen radical–mediated damage.

Detection of Viable Myocardium at MR Imaging
There are several potential ways in which MR contrast media might be used to distinguish viable from infarcted myocardium. Viable myocardium may be identified by labeling necrotic myocardium with necrosis-avid contrast media (45,46). Alternatively, myocardial viability may be inferred with the use of methods to detect breakdown of myocardial cellular membranes (47–49) or with abnormal wash-in–wash-out kinetics (50,51). Direct labeling of normal myocytes by means of uptake of paramagnetic manganese through voltage-dependent Ca2+ channels is a unique feature of delayed Mn-DPDP-enhanced MR imaging.

Limitations
The imaging sequences used in this study—an inversion-recovery echo-planar sequence for the quantification of {Delta}R1 over time and a partially saturated inversion-recovery echo-planar SE sequence for the depiction of regional contrast patterns on high-spatial-resolution images—were the most effective sequences available with our system. However, both sequences have limitations that may render them nonideal for use in patient examinations. The echo-planar images provided low-spatial-resolution depiction of the heart anatomy and, at least with our system, images had notable distortion caused by magnetic field inhomogeneity. Although images obtained at inversion-recovery echo-planar imaging allow accurate quantification of T1 values, they are inappropriate for quantitative morphologic measurements of lesion size.

Inversion-recovery SE imaging provided high-spatial-resolution images that were suitable for morphologic evaluation, but image acquisition was lengthy and offered only single-section coverage with each acquisition. Other sequences likely to provide the requisite T1 sensitivity and coverage in an acceptably short time are inversion-recovery fast gradient-echo and inversion-recovery fast SE sequences, with the caveat that ischemic myocardium may be conspicuous on nonenhanced fully relaxed images obtained with these sequences.

Second, manganese uptake was used to discriminate between viable and reperfused infarcted myocardium, but the specificity of manganese uptake in this discrimination was not examined. Injured but viable myocardium could exhibit uptake and/or retention properties that are different than those of noninjured myocardium. This point could not be confidently addressed by using the animal preparation described previously because the viable portion of the jeopardized myocardium was small after a 60-minute coronary arterial occlusion; it is difficult to distinguish this portion from the infarcted region on images when the infarction is large.Practical applications: The results of this study support the proposition that viable myocardium is selectively enhanced on delayed MR images after the administration of Mn-DPDP. Some of the essential features regarding the dissociation of Mn2+ from Mn-DPDP and the rapid uptake and retention of Mn2+ by viable myocardial cells were well known before this study was initiated. The time course of myocardial cellular uptake of dissociated Mn2+ and the amount of R1 enhancement produced were not known. The current study findings revealed that the uptake process is slow and further showed that contrast enhancement provided by differential cellular function, as probed by Mn2+ uptake in normal and reperfused infarcted myocardium, could be demonstrated on delayed MR images and may be useful to assess myocardial viability with MR imaging.


   FOOTNOTES
 
Abbreviations: CNR = contrast-to-noise ratio, Mn-DPDP = manganese dipyridoxyl diphosphate, NIH = National Institutes of Health, {Delta}R1 = change in R1, SE = spin echo, SI = signal intensity, TI = inversion time

Author contributions: Guarantors of integrity of entire study, C.B.H., M.F.W., M.S.; study concepts, M.F.W., C.B.H., M.S.; study design, M.F.W., M.S., J.B.; definition of intellectual content, C.B.H., M.F.W., M.S.; literature research, M.F.W., J.B.; experimental studies, M.F.W., M.S., J.B., H.A.; data acquisition and analysis, M.F.W., J.B., H.A.; statistical analysis, M.F.W.; manuscript preparation, J.B., M.F.W.; manuscript editing and review, all authors.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
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