Radiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

DOI: 10.1148/radiol.2363040413
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Natanzon, A.
Right arrow Articles by Arai, A. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Natanzon, A.
Right arrow Articles by Arai, A. E.
(Radiology 2005;236:859-866.)
© RSNA, 2005

Experimental Studies

Determining Canine Myocardial Area at Risk with Manganese-enhanced MR Imaging1

Alex Natanzon, MD, Anthony H. Aletras, PhD, Li-Yueh Hsu, DSc and Andrew E. Arai, MD

1 From the Laboratory of Cardiac Energetics, National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services, 10 Center Dr, MSC 1061, Bldg 10, Room B1D-416, Bethesda, MD 20892-1061 (A.N., A.H.A., L.Y.H., A.E.A.); and Mount Sinai School of Medicine, New York, NY (A.N.). Supported by the intramural program of the National Heart, Lung, and Blood Institute. A.N. supported by the Clinical Research Training Program, sponsored by Pfizer, at the National Institutes of Health. Received March 15, 2004; revision requested May 25; revision received November 1; accepted November 12. Address correspondence to A.E.A. (e-mail: araia{at}nih.gov).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To test whether manganese-enhanced magnetic resonance (MR) imaging can safely depict the myocardial area at risk both during coronary artery occlusion and for at least 2 hours after reperfusion in dogs.

MATERIALS AND METHODS: All procedures were performed in accordance with the animal care and use committee of the National Institutes of Health. In eight dogs, the left anterior descending (LAD) coronary artery was occluded for 90 minutes, and 15 µmol of MnCl2 per kilogram of body weight was intravenously infused for 12 minutes. Phase-sensitive inversion-recovery MR imaging of the LAD arterial territory was performed before occlusion, during MnCl2 infusion, and for at least 2 hours after reperfusion. Hemodynamic responses were monitored continuously. Fluorescent microsphere enhancement was used as the reference standard for determining the area at risk ex vivo. Results are reported as percentages of left ventricular area. Correlation, Bland-Altman, and t test analyses were performed.

RESULTS: Significant differences in manganese-induced contrast enhancement of the area at risk, the normal myocardium, and the blood (P < .01) were measured during LAD artery occlusion and at least 2 hours after reperfusion. No significant changes in heart rate or blood pressure were detected during or after MnCl2 infusion. Measurements of the area at risk obtained with manganese-enhanced MR imaging during LAD artery occlusion and 2 hours after reperfusion correlated well with the size of the at-risk area demarcated by the fluorescent microspheres (during occlusion: y = 0.81x, R = 0.90; during reperfusion: y = 0.83x, R = 0.89). Bland-Altman analysis revealed small systematic errors in measurements at both occlusion and reperfusion.

CONCLUSION: Manganese-enhanced MR imaging can depict the area at risk during LAD artery occlusion and at least 2 hours after reperfusion without hemodynamic compromise.

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
In myocardial viability assessments and trials to assess therapies that reduce infarct size, two concepts are important: First, the amount of myocardium that ultimately becomes irreversibly injured or infarcted is a subset of the area at risk, which is defined as the total area of the myocardium that experiences a substantial perfusion deficit (1–3). Second, because of the variability in coronary anatomy, the presence of collateral vessels, and the severity or duration of ischemia, the relationship between the infarct size and the area at risk has been used extensively to establish internal controls in studies aimed at modulating infarct size. Thus, accurate assessment of the area at risk in cases of acute myocardial infarction is important in basic science studies and could be clinically useful. For example, comparing the area at risk with the area of actual infarction enables one to quantify the amount of salvaged myocardium (4,5) and assess the treatment benefit in individual patients (5–7). The measured size of salvaged myocardium may also be used as an end point in comparisons of different revascularization techniques (6).

The noninvasive assessment of the myocardial area at risk has been studied by using single photon emission computed tomography (SPECT) with technetium 99m (99mTc) sestamibi (6). After 99mTc-sestamibi is intravenously injected, it enters the normal myocardium in direct proportion to the blood flow (8). Once 99mTc-sestamibi is intracellular, it has a very slow washout rate, which is not dependent on myocardial blood flow (8). Because of its pharmacokinetic properties, 99mTc-sestamibi can be administered when a patient who has had an acute myocardial infarction initially presents to the emergency department, and imaging of the area at risk can be performed hours later, after the patient has been treated and stabilized (5,7).

Manganese is a paramagnetic ion with pharmacokinetic properties similar to those of 99mTc-sestamibi. Manganese cations enter normal cardiac myocytes through voltage-gated calcium channels and remain there for several days (9). Manganese ion uptake is decreased in the infarcted myocardium (10,11) and in ischemic but viable myocardium (12). Although manganese has been tested as a marker of viability, its effectiveness for use as a contrast agent similar to the agents used in nuclear medicine has not to our knowledge been explored. Manganese potentially could be injected during an infarction in progress and may have a duration of enhancement that is long enough to allow imaging of the area at risk at a later time, when reperfusion may have occurred.

In this study, our purpose was to determine whether cardiac magnetic resonance (MR) imaging with MnCl2 infused during coronary artery occlusion can depict the area at risk during the occlusion and for at least 2 hours after reperfusion in a canine model.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Animal Preparation
All procedures were performed in accordance with the animal care and use committee of the National Institutes of Health. Eight beagles with an average weight of 10 kg were anesthetized with subcutaneously administered acepromazine (0.2 mg per kilogram of body weight), intravenously administered thiopental sodium (15 mg/kg), and 0.5%–2.0% inhaled isoflurane. Surgical preparation included the insertion of an 8-F left jugular Hickman catheter (Bard Access Systems, Salt Lake City, Utah), a 6.6-F left atrial appendage Broviac infusion catheter (Bard Access Systems), a femoral arterial line, and a balloon occluder in the middle or proximal left anterior descending (LAD) coronary artery.

Study Protocol
A technician induced myocardial infarction in the dogs by totally occluding the LAD coronary artery (13). A single intravenous infusion of MnCl2 was started 3–5 minutes later: 4 mmol/L at 3.1 mL/min was infused for 12 minutes for a total dose of 15 µmol/kg. The LAD coronary artery was reperfused after a total occlusion time of 90 minutes. Continuous blood pressure and heart rate monitoring was performed throughout the experiment.

Cardiac MR Imaging
MR imaging was performed (by A.N. and A.H.A.) by using a 1.5-T magnet (CV/i; GE Medical Systems, Milwaukee, Wis) with a standard four-element phased-array knee coil. Functional cine loops (14) were acquired along the short and long axes with steady-state free precession (15,16) before, during, and 2 hours after the LAD coronary artery occlusion. The entire left ventricle (LV) was imaged by using a two-dimensional phase-sensitive inversion-recovery fast gradient-recalled-echo pulse sequence with interleaved phase-encode ordering (17). Multiple two-dimensional short-axis images were acquired by using the following parameters: 7.8/3.4/350 (repetition time msec/echo time msec/inversion time msec), a bandwidth of ±32 kHz, 12 lines of k-space per image segment, an acquisition window of 93.6 msec, an in-plane spatial resolution of 1.0 x 0.9 mm, a section thickness of 8 mm (17), and no intersection gap. Data acquisition was initiated every four heartbeats to allow longitudinal relaxation.

To study kinetics, in all eight dogs one section was imaged approximately every 2 minutes throughout the experiment. Therefore, single-section images were acquired before any intervention was performed and up to 2 hours after reperfusion. Volumetric MR imaging of the heart was performed during the LAD coronary artery occlusion, 60 minutes after the MnCl2 infusion was stopped, and 2 hours after the occlusion was stopped. Imaging involved multiple acquisitions of two-dimensional MR images of the entire LV, from the base to the apex, in a short-axis imaging plane; six or seven sections per animal were acquired with no intersection gap. In one dog, owing to acquisition problems, volumetric imaging was not completed during the occlusion.

Myocardial Tissue Processing
The animals were euthanized 6 hours after reperfusion. Five minutes before they were sacrificed, the LAD coronary artery was occluded again and 100 mg of fluorescent microspheres (Duke Scientific, Palo Alto, Calif) was injected through the left atrial appendage catheter (18). The dogs were then sacrificed with a lethal injection of potassium chloride after intravenous heparin (10 000 U) administration. The excised hearts were rinsed with normal saline and sliced into 4-mm sections by using a commercially available meat slicer (Globe Food Equipment, Dayton, Ohio). Two authors (A.N., A.H.A.) photographed each slice under ultraviolet light to visualize the fluorescent microspheres and delineate the area at risk. Subsequently, each slice was stained with triphenyltetrazolium chloride (TTC) (by A.N. and A.E.A.) for demarcation of the infarcted myocardial region (19). The TTC-stained slices were submerged in 0.9% normal saline and photographed (by A.N., A.H.A., and A.E.A.).

Image Analysis
The MR imaging sections were matched to the ex vivo heart slices by consensus (among A.N., A.H.A., and A.E.A., with 1, 7, and 10 years of experience in cardiac MR imaging, respectively) on the basis of anatomic characteristics, which included the shape of the LV, the shape and location of the papillary muscle, and the insertion point of the right ventricle. For each dog, four consecutive MR imaging sections were matched to eight consecutive ex vivo heart slices; this yielded a 32-mm area of volumetric coverage of the LV mass. For slice-by-slice comparisons, the four best-aligned ex vivo slices (now 8 mm apart) were correlated against the four consecutive MR imaging sections (with 8-mm separation). On all imaging sections, the LV area was manually traced (by A.N.) by using the Cine Display Application, version 2.1 (GE Medical Systems and the National Heart, Lung, and Blood Institute), program, and the area at risk was calculated as a percentage of the LV. The mean signal intensity was calculated by measuring the normal myocardium, the area at risk, and the LV blood pool (by A.N.).

On all photographs of the fluorescent microspheres, the area at risk was manually measured (by A.N.). On all TTC-stained slices, the infarcted myocardium was quantified (by L.H., with 2 years of experience in cardiac MR image analysis and 10 years of experience in medical image processing) by using an automated computer algorithm (20). This program automatically computes threshold values to separate the bimodal signal intensity distributions of normal myocardial tissue and infarcted myocardial tissue image pixels. The contrast material–enhanced region is then analyzed by using feature-based image-processing methods. On all MR images, the area at risk was quantified by using volumetric assessment of the LV by the same computer program but with different settings.

Statistical Analyses
Linear regression and Bland-Altman analyses were used to compare the area at risk depicted on the MR images with the area at risk seen on the anatomic slices. Paired two-tailed t tests with Bonferroni correction were used to compare the signal intensity seen before, during, and after MnCl2 infusion. A paired two-tailed Student t test was used to compare the size of the infarcted area on the TTC-stained anatomic slices with the size of the area at risk seen on the microsphere-enhanced anatomic slices and the MR image sections. A paired two-tailed Student t test with Bonferroni correction was also used to compare the patients' systolic blood pressure, diastolic blood pressure, and heart rate at baseline, during LAD artery occlusion prior to the MnCl2 infusion, during the MnCl2 infusion, after the MnCl2 infusion with the LAD artery occlusion still in progress, and 2 hours after reperfusion.

It was determined that with the sample size used, we would be able to observe a correlation of 0.85 or higher with an {alpha} of .05 and a power of 0.80 or better. This sample size was also selected so that we would be able to detect a 15% change in signal intensity at paired t testing with the assumption of 10% variability in the differences at an {alpha} of .05 and a power of 0.80. Values are reported as means ± standard errors of the mean, unless otherwise noted. A significant difference was indicated by a P value of less than or equal to .05. All calculations were performed with Sigma Stat, version 2.03, software (SPSS, Chicago, Ill).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Demarcation of At-Risk Area with Manganese-enhanced Cardiac MR Imaging
The findings of one MR imaging experiment are shown in Figure 1. There was no substantial difference in signal intensity between the area at risk and the normal myocardium either before the occlusion (data not shown) or during the first minutes of the occlusion before the MnCl2 infusion (Fig 1, A). During the MnCl2 infusion, while the LAD coronary artery was occluded, the normal myocardium became enhanced, the area at risk remained hypointense (Fig 1, B), and the blood had the highest signal intensity. After the infusion was discontinued, the manganese rapidly cleared from the bloodstream and the signal intensity of the blood became lower than that of the normal myocardium (Fig 1, C, D). Early (Fig 1, E) and 2 hours (Fig 1, F) after reperfusion, the area at risk retained a signal intensity that was lower than that of the normal myocardium and higher than that of the blood. Qualitatively, there was good contrast between the area at risk and both the normal myocardium and the blood throughout the experiment.



View larger version (173K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 1. Representative phase-sensitive inversion-recovery fast gradient-recalled-echo MR images (7.8/3.4/350; voxel size, 1.0 x 0.9 x 8.0 mm) of myocardial regions obtained before, during, and after MnCl2 infusion in a short-axis plane at the midventricular level. A, LAD artery occlusion before MnCl2 infusion. B, At MnCl2 infusion during LAD artery occlusion, blood in the LV shows maximum signal intensity. Arrow points to the area at risk. C, Immediately after MnCl2 infusion, when the blood pool MnCl2 is washing out and the LAD artery is occluded. D, Just prior to reperfusion. E, Seventy-five minutes after MnCl2 infusion, immediately after LAD artery occlusion has been stopped. F, Three hundred minutes after MnCl2 infusion and 120 minutes after LAD artery occlusion has been stopped. With infusion of MnCl2, the area at risk was demarcated during LAD artery occlusion and at least 2 hours after reperfusion.

 
The time course of the changes in signal intensity of the LV blood, the normal myocardium, and the area at risk seen on the MR images shown in Figure 1 is depicted in Figure 2. After the MnCl2 infusion, the normal myocardium, the area at risk, and the blood had three distinct ranges of signal intensity, and these differences persisted at least 2 hours after the occlusion ended.



View larger version (29K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 2. Graphs illustrate time course of manganese (Mn)-induced enhancement in the LV blood, the area at risk, and the normal myocardium in the canine experiments. Horizontal bars indicate the timing of occlusion and of MnCl2 infusion. The blood in the LV cavity (top graph) shows a rapid increase and then rapid decrease in signal intensity. The normal myocardium (bottom graph, {blacktriangleup}) shows an increase in signal intensity that remains elevated at 200 minutes after the beginning of the MnCl2 infusion. The area at risk (bottom graph, {triangleup}) shows relatively little change in signal intensity throughout the experiment. A.U. = arbitrary units.

 
In terms of group averages for the eight dogs (Fig 3), there was no significant difference in signal intensity between the normal and the ischemic myocardial regions before the MnCl2 infusion (P = .79). During the infusion, the normal myocardium, as measured on the phase-sensitive inversion-recovery MR images, became dramatically enhanced (from a mean of –2484 ± 194 to a mean of 154 ± 185, P < .001), whereas there was a minimal change in signal intensity in the area at risk (from a mean of –2500 ± 212 to a mean of –2297 ± 220, P = .19). At all time points during the experiment after MnCl2 was administered, the normal myocardium had significantly higher signal intensity than it did at baseline (P < .001) and it remained brighter than the area at risk (P < .001). This difference persisted for at least 2 hours after the occlusion was stopped, or approximately 3 hours after the completion of the MnCl2 infusion (Fig 3). The area at risk remained brighter than the blood in the LV at all time points after the washout of manganese from the blood (data not shown, P = .001 immediately and P < .001 2 hours after the occlusion was stopped). The signal intensity of the area at risk did not change significantly throughout the experiment.



View larger version (26K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 3. Bar graph illustrates degrees of contrast enhancement of the area at risk and of the normal myocardium at different stages of the experiment in eight dogs. The area at risk and the normal myocardium exhibit no significant difference in signal intensity before the MnCl2 (Mn) infusion. After the infusion, the area at risk and the normal myocardium show a significant difference in signal intensity throughout the rest of the experiment. MnCl2 administration did not cause a significant increase in the signal intensity of the area at risk. A.U. = arbitrary units, Occl+Mn = LAD coronary artery occluded during MnCl2 infusion, Occl-PostMn = LAD coronary artery occluded 60 minutes after MnCl2 infusion stopped, Pre-Mn = LAD coronary artery occluded before MnCl2 infusion started, Reperf-1 = 5 minutes after LAD coronary artery occlusion stopped, Reperf-2 = 120 minutes after LAD coronary artery occlusion stopped.

 
Comparison between At-Risk Area and Infarcted Myocardium at MR Imaging and Histopathologic Analysis
The area at risk was demarcated with both manganese-enhanced MR imaging and the fluorescent microspheres (Fig 4). Qualitatively, the size of the area at risk looked similar in vivo on the manganese-enhanced MR images and ex vivo on the fluorescent microsphere–enhanced slices (Fig 4, middle image). The infarcted area was smaller, as seen on the TTC-stained slices (Fig 4, left image). Bland-Altman and correlation analyses were used to quantitatively compare the area at risk measured on the manganese-enhanced MR images with the area at risk measured on the ex vivo fluorescent microsphere–enhanced slices (Fig 5). The areas at risk during occlusion (y = 0.81x, R = 0.90; P < .001) and 2 hours after reperfusion (y = 0.83x, R = 0.89; P < .001) were compared. Bland-Altman analysis revealed systematic errors in measurements obtained during occlusion and 2 hours after reperfusion of –3.23% of the LV ± 10.4 (standard deviation) and –3.22% of the LV ± 11.4 (standard deviation), respectively.



View larger version (37K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 4. Comparison of TTC-stained myocardium (left), myocardial area at risk demarcated by fluorescent microspheres (middle), and in vivo manganese-enhanced MR image (right) corresponding anatomically to the two (left and middle) histopathologic slices. Left: On the TTC-stained specimen, the normal myocardium is stained red and the infarcted region appears as white subendocardial patches. Middle: Fluorescent microspheres injected at the time of the occlusion demarcate the perfused myocardium, which appears yellowish green, and thus generate contrast between the normal myocardium and the area at risk (borders indicated by arrows). At 90 minutes of occlusion in these dogs, the infarcted region encompasses only a small percentage of the area at risk, which is largely transmural according to the region demarcated by the fluorescent microspheres. Right: In vivo manganese-enhanced phase-sensitive inversion-recovery fast gradient-recalled-echo MR image (7.8/3.4/350; voxel size, 1.0 x 0.9 x 8.0 mm) obtained in the short-axis plane at the midventricular level 2 hours after reperfusion, approximately 3 hours after MnCl2 administration. The area at risk starts in the anterior septum and extends through the anterior and anterolateral walls (borders indicated by arrows).

 


View larger version (38K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 5a. (a) Graph illustrates correlation between manganese (Mn)-enhanced MR imaging and fluorescent microsphere measurements of the size of the area at risk during and after LAD coronary artery occlusion. (b) Bland-Altman plot of manganese-enhanced MR imaging and fluorescent microsphere measurements of the size of the area at risk during and after LAD coronary artery occlusion. There was a good agreement between the area at risk measured with manganese-enhanced MR imaging and that measured with fluorescent microspheres. SD = standard deviation.

 


View larger version (37K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 5b. (a) Graph illustrates correlation between manganese (Mn)-enhanced MR imaging and fluorescent microsphere measurements of the size of the area at risk during and after LAD coronary artery occlusion. (b) Bland-Altman plot of manganese-enhanced MR imaging and fluorescent microsphere measurements of the size of the area at risk during and after LAD coronary artery occlusion. There was a good agreement between the area at risk measured with manganese-enhanced MR imaging and that measured with fluorescent microspheres. SD = standard deviation.

 
The area at risk measured by using either manganese-enhanced MR imaging or the fluorescent microspheres was larger than the infarcted area seen on the TTC-stained slices (P < .002) (Fig 6). The size of the area at risk depicted on the manganese-enhanced MR images did not change significantly between the images obtained during coronary artery occlusion and those obtained 2 hours after reperfusion (P = .82). The size of the area at risk was not significantly different at comparisons between the manganese-enhanced MR images obtained at either time point and the fluorescent microsphere–enhanced myocardial slices (P = .18 during occlusion, P = .18 2 hours after reperfusion).



View larger version (29K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 6. Bar graph shows that the size of the abnormality depicted on the manganese-enhanced MR images (During Occlusion and After Reperfusion) was larger than the infarcted region measured on the TTC-stained slices (P < .002) but not significantly different from the area at risk demarcated on the fluorescent microsphere–enhanced slices.

 
Effect of MnCl2 Administration on Hemodynamic Status
For all dogs examined in the study, the mean heart rate throughout the experiment was 104 beats per minute ± 5. The hemodynamic data for all the dogs used in the experiment are summarized in Figure 7. LAD artery occlusion caused significant decreases in the mean systolic blood pressure, from 102 mm Hg ± 5 to 88 mm Hg ± 4 (P = .01), and in the mean diastolic blood pressure, from 62 mm Hg ± 4 to 56 mm Hg ± 3 (P = .01). The mean blood pressure did not change significantly during either the MnCl2 infusion (for systolic blood pressure, from 88 mm Hg ± 4 to 86 mm Hg ± 3 [P = .38]; for diastolic blood pressure, from 56 mm Hg ± 3 to 55 mm Hg ± 3 [P = .25]) or the first 5 minutes after the infusion was stopped (for systolic blood pressure, 88 mm Hg ± 4 [P = .16]; for diastolic blood pressure, 57 mm Hg ± 4 [P = .93]). Two hours after the occlusion was stopped (approximately 3 hours after the MnCl2 infusion), the mean blood pressure was similar to that observed during the MnCl2 infusion (for systolic blood pressure, 85 mm Hg ± 6 [P = .5]; for diastolic blood pressure, 53 mm Hg ± 5 [P = .36]).



View larger version (27K):
[in this window]
[in a new window]
[Download PPT slide]
  		Figure 7. Graph illustrates blood pressure and heart rate measurements at five time points during the experiment. LAD coronary artery occlusion caused a significant (P < .01) decrease in systolic and diastolic blood pressures. MnCl2 (Mn) infusion had no significant effect on blood pressure. Two hours after reperfusion, the systolic and diastolic blood pressures were similar to those observed before the start of the MnCl2 infusion. There was no significant change in the heart rate throughout the LAD artery occlusion or the MnCl2 infusion or during the first 5 minutes after the infusion was stopped. Two hours after reperfusion, the heart rate was slightly higher than it was at the start of the MnCl2 infusion. bpm = beats per minute.

 
The LAD artery occlusion caused a small decrease in the mean heart rate (from 104 beats per minute ± 6 to 101 beats per minute ± 4, P = .48). The mean heart rate did not change significantly during either the MnCl2 infusion (101 beats per minute ± 5, P = .88) or the first 5 minutes after the infusion had ended (101 beats per minute ± 5, P = .87). Two hours after the occlusion was stopped (approximately 3 hours after the MnCl2 infusion), the mean heart rate was slightly elevated compared with that observed during the MnCl2 infusion (110 beats per minute ± 5, P = .03).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
Manganese-enhanced cardiac MR imaging can depict the area at risk during total coronary artery occlusion and yield measurable images at least 2 hours after reperfusion without causing adverse hemodynamic effects. It is important to recognize that rather than depict only the infarcted myocardium, manganese-enhanced MR images can show the more extensive region that includes the periinfarcted ischemic zone. During the occlusion of a coronary vessel, the area at risk represents that portion of the myocardium with substantially decreased perfusion. The infarcted area, if present, represents a subset, of the area at risk, that becomes necrotic because of prolonged ischemia (1–3). The duration of ischemia is an important factor in determining how much of the area at risk will become infarcted. If the duration of the occlusion is short (ie, less than 15 minutes), then no tissue within the area at risk will become necrotic (21). Thus, the manganese-enhanced MR imaging examination described in this article is distinct from but complementary to delayed-enhancement cardiac MR imaging viability techniques, with which specifically the infarcted myocardium is imaged. Furthermore, in the current study, the intravenous infusion of 15 µmol/kg MnCl2 over the course of 12 minutes did not result in marked changes in blood pressure or heart rate.

The size of the area at risk during occlusion and 2 hours after reperfusion that was measured with manganese-enhanced MR imaging correlated well with the size of the area at risk that was delineated by using the fluorescent microspheres. Fluorescent microspheres have been routinely used as a reference standard for demarcating the area at risk in studies of ischemic preconditioning (22,23) and in a study on myocardial infarction (18).

Conceptually, the difference between prior experiments and the current work is related to the timing of the manganese-based agent administration and the reperfusion status of the infarcted area. In most studies, a manganese-based agent has been administered in either a nonreperfused infarcted region model or after reperfusion (11,24–27). In nonreperfused infarcted regions (25,27), the infarcted region and the area of the perfusion defect are roughly equivalent, and measurements of the two areas are similar in size. When the manganese-based contrast agent is administered after reperfusion (11,24,26), viable myocardial tissue accumulates manganese and becomes enhanced whereas the infarcted myocardium does not become enhanced. In these two scenarios, the infarcted region and the area of the manganese defect appear to be the same size.

In the current experiments, by administering MnCl2 during the occlusion and infusing a dose that was small enough to clear from the bloodstream before reperfusion, we generated a record of the size of the perfusion defect during the occlusion—that is, the area at risk. The infarcted region was a subset of the area at risk and thus was smaller than the manganese defect.

In terms of safety, manganese is an important component of human metabolism. It plays a role in the metabolism of catecholamines (28), the metabolism and function of mitochondria (29,30), and the synthesis of mucopolysaccharides (31). Manganese is a dietary component, and the daily intake of this element is 2–6 mg (29). For a man with an average weight of 70 kg, the daily intake of manganese from food is 0.53–1.60 µmol/kg. In comparison, the manganese-based contrast agent, mangafodipir trisodium (Teslascan; Nycomed Amersham, Oslo, Norway), is U.S. Food and Drug Administration approved for imaging the liver at a dose of 5 µmol/kg (32,33).

Interest in manganese-enhanced cardiac MR imaging has been limited owing to concerns regarding its effects on cardiac function. Manganese competes with calcium for entry into the cardiac myocyte through the voltage-gated calcium channels (34). Wolf and Baum found that 10–100 µmol/kg MnCl2 injected intravenously into dogs and rabbits over the course of 30 seconds caused a decrease in blood pressure, an increase or decrease in heart rate, and prolonged R-R, P-R, and QT intervals (35). However, these findings may have been due to the relatively fast rate of infusion (30 seconds). When Goldman et al injected 50 µmol/kg MnCl2 over the course of 5 minutes, no adverse hemodynamic events were observed (25). Other previous work has revealed that the injection of 11 and 36 µmol/kg MnCl2 for 3 minutes causes enhancement of the contrast between normal and ischemic myocardial tissue without negative hemodynamic effects (36). In the current study, the infusion of 15 µmol/kg MnCl2 for 12 minutes also resulted in no adverse effects on heart rate or blood pressure.

It has been suggested that manganese-related cardiac toxicity may be the result of an acute elevation of extracellular rather than intracellular levels of free ions (37). There may be a threshold for the extracellular level of free manganese ions beyond which cardiac toxicity occurs. The slow infusion of MnCl2 may allow sufficient time for the cardiac uptake and the blood clearance of free manganese ions before their extracellular levels reach such a threshold of toxicity.

The kinetics of MnCl2 infused over the course of minutes may replicate the normal kinetics of manganese dipyridoxyl diphosphate. When manganese dipyridoxyl diphosphate is injected into the circulation, manganese is released from the chelate slowly, and it may take hours for the ions to accumulate in the heart (11,38). Because of these pharmokinetic properties, a manganese dipyridoxyl diphosphate dose as high as 400 µmol/kg can be injected without causing adverse hemodynamic events (39).

The potential for manganese infusion to cause prolonged R-R, P-R, and Q-T intervals, as reported by Wolf and Baum (35), also is important. It is possible that the rhythm changes observed by Wolf and Baum were caused by the rapid administration of MnCl2. Karlsson et al (40) intravenously injected 1, 6, and 30 µmol/kg MnCl2 over the course of 15 minutes into mongrels with experimentally induced acute ischemic heart failure. They observed a nonsubstantial increase in the QT interval in association with the 30 µmol/kg dose and no cardiac arrhythmias in association with any of the doses studied. Kligfield et al (41) reported that MnCl2 administered over the course of 5 minutes to dogs with myocardial infarction exhibited the important antiarrhythmic property of being able to decrease the rate of premature ventricular contractions.

Manganese, in the form of radioactive isotopes (manganese 54m and manganese 52m), has also been studied as a potential myocardial perfusion tracer for positron emission tomography (42–44). To our knowledge, no adverse cardiac events have been reported in the animal studies performed by using these agents.

Other adverse health effects that are possibly associated with manganese exposure include Parkinson disease (45) and neuropsychiatric symptoms (46). These effects have been described in people who were chronically exposed to elevated airborne levels of manganese. Because injected manganese doses are similar to the recommended daily intake of this agent, long-term effects seem to be unlikely.

Because of our study design, magnetohydrodynamic effects prevented us from monitoring the effects of MnCl2 administration on electrocardiographic findings (47,48). Nevertheless, no substantial arrhythmias were detected during the slow infusion of MnCl2.

A number of limiting factors affected our correlation analysis of the area at risk seen on MR images versus that seen at histopathologic analysis. These factors included partial volume effects, the low spatial resolution of the images, and registration imperfections that are inevitable when MR images are compared with histopathologic specimens. Nonetheless, our comparisons of the areas at risk still revealed strong correlations and good agreement at Bland-Altman analysis.

Practical applications: Similar to SPECT with 99mTc-sestamibi, manganese-enhanced cardiac MR imaging can be used to quantify the area at risk in patients with ischemic heart disease. SPECT can be used to quantify the amount of infarcted myocardium (49,50). Comparing the area at risk with the area of infarcted myocardium yields a measurement of the area of salvaged myocardium. Cardiac MR imaging offers several advantages over 99mTc-sestamibi imaging, including higher spatial resolution (51) and freedom from scattering and attenuation artifacts (52). Cardiac MR imaging with delayed gadolinium-induced increased enhancement is accurate for the depiction and quantification of acute myocardial infarction (53). Previous injection of a manganese-based contrast agent does not preclude gadolinium-enhanced MR imaging. Thus, cardiac MR imaging enables one to quantify the area at risk and the area of infarcted myocardium during a single examination. In addition, the same examination can yield information about the anatomy (54), function (55), and perfusion of the myocardium (56).


   ACKNOWLEDGMENTS
 
The authors thank Joni Taylor, BS, Gina Orcino, BS, and Diana Lancaster, BS, for animal care and preparation.


   FOOTNOTES
 

Abbreviations: LAD = left anterior descending • LV = left ventricle • TTC = triphenyltetrazolium chloride

Authors stated no financial relationship to disclose.

Author contributions: Guarantors of integrity of entire study, A.E.A., A.H.A.; study concepts, all authors; study design, A.N., A.E.A., A.H.A.; literature research, A.N.; experimental studies, all authors; data acquisition, A.N., A.E.A., A.H.A.; data analysis/interpretation, all authors; statistical analysis, A.N., L.Y.H., A.E.A.; manuscript preparation, definition of intellectual content, editing, revision/review, and final version approval, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

  1. Saeed M, Bremerich J, Wendland MF, Wyttenbach R, Weinmann HJ, Higgins CB. Reperfused myocardial infarction as seen with use of necrosis-specific versus standard extracellular MR contrast media in rats. Radiology 1999;213:247–257.[Abstract/Free Full Text]
  2. Horstick G, Heimann A, Gotze O, et al. Intracoronary application of C1 esterase inhibitor improves cardiac function and reduces myocardial necrosis in an experimental model of ischemia and reperfusion. Circulation 1997;95:701–708.[Abstract/Free Full Text]
  3. Okamura T, Miura T, Iwamoto H, et al. Ischemic preconditioning attenuates apoptosis through protein kinase C in rat hearts. Am J Physiol 1999; 277(5 pt 2):H1997–H2001.
  4. Miller TD, Christian TF, Hopfenspirger MR, Hodge DO, Gersh BJ, Gibbons RJ. Infarct size after acute myocardial infarction measured by quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality. Circulation 1995;92:334–341.[Abstract/Free Full Text]
  5. Santoro GM, Bisi G, Sciagra R, Leoncini M, Fazzini PF, Meldolesi U. Single photon emission computed tomography with technetium-99m hexakis 2-methoxyisobutyl isonitrile in acute myocardial infarction before and after thrombolytic treatment: assessment of salvaged myocardium and prediction of late functional recovery. J Am Coll Cardiol 1990;15:301–314.[Abstract]
  6. Gibbons RJ. Technetium 99m sestamibi in the assessment of acute myocardial infarction. Semin Nucl Med 1991;21:213–222.[CrossRef][Medline]
  7. Wackers FJ, Gibbons RJ, Verani MS, et al. Serial quantitative planar technetium-99m isonitrile imaging in acute myocardial infarction: efficacy for noninvasive assessment of thrombolytic therapy. J Am Coll Cardiol 1989;14:861–873.[Abstract]
  8. Okada RD, Glover D, Gaffney T, Williams S. Myocardial kinetics of technetium-99m-hexakis-2-methoxy-2-methylpropyl-isonitrile. Circulation 1988;77:491–498.[Abstract/Free Full Text]
  9. Maynard LS, Cotzias GC. The partition of manganese among organs and intracellular organelles of the rat. J Biol Chem 1955;214:489–495.[Free Full Text]
  10. Wendland MF, Saeed M, Geschwind JF, Mann JS, Brasch RC, Higgins CB. Distribution of intracellular, extracellular, and intravascular contrast media for magnetic resonance imaging in hearts subjected to reperfused myocardial infarction. Acad Radiol 1996; 3(suppl 2):S402–S404.
  11. Bremerich J, Saeed M, Arheden H, Higgins CB, Wendland MF. Normal and infarcted myocardium: differentiation with cellular uptake of manganese at MR imaging in a rat model. Radiology 2000;216:524–530.[Abstract/Free Full Text]
  12. Krombach GA, Saeed M, Higgins CB, Novikov V, Wendland MF. Contrast-enhanced MR delineation of stunned myocardium with administration of MnCl(2) in rats. Radiology 2004;230:183–190.[Abstract/Free Full Text]
  13. Weiss CR, Aletras AH, London JF, et al. Stunned, infarcted, and normal myocardium in dogs: simultaneous differentiation by using gadolinium-enhanced cine MR imaging with magnetization transfer contrast. Radiology 2003;226:723–730.[Abstract/Free Full Text]
  14. Feinstein JA, Epstein FH, Arai AE, et al. Using cardiac phase to order reconstruction (CAPTOR): a method to improve diastolic images. J Magn Reson Imaging 1997;7:794–798.[Medline]
  15. Carr HY. Steady-state free precession in nuclear magnetic resonance. Phys Rev 1958;112:1693–1701.[CrossRef]
  16. Oppelt A, Graumann R, Barfuss H, Fischer H, Hartl W, Shajor W. FISP: a new fast MRI sequence. Electromedica 1986;54:15–18.
  17. Kellman P, Arai AE, McVeigh ER, Aletras AH. Phase-sensitive inversion recovery for detecting myocardial infarction using gadolinium-delayed hyperenhancement. Magn Reson Med 2002;47:372–383.[CrossRef][Medline]
  18. Rehwald WG, Fieno DS, Chen EL, Kim RJ, Judd RM. Myocardial magnetic resonance imaging contrast agent concentrations after reversible and irreversible ischemic injury. Circulation 2002;105:224–229.[Abstract/Free Full Text]
  19. Fishbein MC, Meerbaum S, Rit J, et al. Early phase acute myocardial infarct size quantification: validation of the triphenyl tetrazolium chloride tissue enzyme staining technique. Am Heart J 1981;101:593–600.[CrossRef][Medline]
  20. Hsu L, Natanzon A, Aletras AH, Kellman P, Arai AE. Automated quantitative myocardial infarct sizing: in vivo and ex vivo correlation with histopathology. Presented at the Society of Magnetic Resonance Seventh Annual Scientific Sessions, Barcelona, Spain, February 13–15, 2005.
  21. Canty JM, Fallavollita JA. Chronic hibernation and chronic stunning: a continuum. J Nucl Cardiol 2000;7:509–527.[CrossRef][Medline]
  22. Cope DK, Impastato WK, Cohen MV, Downey JM. Volatile anesthetics protect the ischemic rabbit myocardium from infarction. Anesthesiology 1997;86:699–709.[Medline]
  23. Shattock MJ, Lawson CS, Hearse DJ, Downey JM. Electrophysiological characteristics of repetitive ischemic preconditioning in the pig heart. J Mol Cell Cardiol 1996;28:1339–1347.[CrossRef][Medline]
  24. Brady TJ, Goldman MR, Pykett IL, et al. Proton nuclear magnetic resonance imaging of regionally ischemic canine hearts: effect of paramagnetic proton signal enhancement. Radiology 1982;144:343–347.[Abstract/Free Full Text]
  25. Goldman MR, Brady TJ, Pykett IL, et al. Quantification of experimental myocardial infarction using nuclear magnetic resonance imaging and paramagnetic ion contrast enhancement in excised canine hearts. Circulation 1982;66:1012–1016.[Abstract/Free Full Text]
  26. Wendland MF, Saeed M, Bremerich J, Arheden H, Higgins CB. Thallium-like test for myocardial viability with MnDPDP-enhanced MRI. Acad Radiol 2002; 9(suppl 1):S82–S83.
  27. Flacke S, Allen JS, Chia JM, et al. Characterization of viable and nonviable myocardium at MR imaging: comparison of gadolinium-based extracellular and blood pool contrast materials versus manganese-based contrast materials in a rat myocardial infarction model. Radiology 2003;226:731–738.[Abstract/Free Full Text]
  28. Cotzias GC, Papavasiliou PS, Mena I, Tang LC, Miller ST. Manganese and catecholamines. Adv Neurol 1974;5:235–243.[Medline]
  29. Cotzias GC. Manganese in health and disease. Physiol Rev 1958;38:503–532.[Free Full Text]
  30. Hurley LS, Theriault LL, Dreosti IE. Liver mitochondria from manganese-deficient and pallid mice: function and ultrastructure. Science 1970;170:1316–1318.[Abstract/Free Full Text]
  31. Leach RM Jr. Role of manganese in mucopolysaccharide metabolism. Fed Proc 1971;30:991–994.[Medline]
  32. Rummeny E, Ehrenheim C, Gehl HB, et al. Manganese-DPDP as a hepatobiliary contrast agent in the magnetic resonance imaging of liver tumors: results of clinical phase II trials in Germany including 141 patients. Invest Radiol 1991; 26(suppl 1):S142–S145.
  33. Gehl HB, Urhahn R, Bohndorf K, et al. Mn-DPDP in MR imaging of pancreatic adenocarcinoma: initial clinical experience. Radiology 1993;186:795–798.[Abstract/Free Full Text]
  34. Vander Elst L, Colet JM, Muller RN. Spectroscopic and metabolic effects of MnCl2 and MnDPDP on the isolated and perfused rat heart. Invest Radiol 1997; 32:581–588.[CrossRef][Medline]
  35. Wolf GL, Baum L. Cardiovascular toxicity and tissue proton T1 response to manganese injection in the dog and rabbit. AJR Am J Roentgenol 1983;141:193–197.[Abstract/Free Full Text]
  36. Hu T, Christian TF, Aletras AH, Taylor JL, Koretsky AP, Arai AE. Manganese enhanced MRI of normal and ischemic canine heart. Magn Reson Med (in press).
  37. Brurok H, Schjott J, Berg K, Karlsson JO, Jynge P. Manganese and the heart: acute cardiodepression and myocardial accumulation of manganese. Acta Physiol Scand 1997;159:33–40.[CrossRef][Medline]
  38. Gallez B, Baudelet C, Adline J, Charbon V, Lambert DM. The uptake of Mn-DPDP by hepatocytes is not mediated by the facilitated transport of pyridoxine. Magn Reson Imaging 1996;14:1191–1195.[CrossRef][Medline]
  39. Pomeroy OH, Wendland M, Wagner S, et al. Magnetic resonance imaging of acute myocardial ischemia using a manganese chelate, Mn-DPDP. Invest Radiol 1989;24:531–536.[CrossRef][Medline]
  40. Karlsson JO, Mortensen E, Pedersen HK, Sager G, Refsum H. Cardiovascular effects of MnDPDP and MnCl2 in dogs with acute ischaemic heart failure. Acta Radiol 1997;38:750–758.[Medline]
  41. Kligfield P, Charash B, Placek E, Sos TA. Antiarrhythmic effect of manganese chloride in infarcted dogs with observations on the dose-related response of heart rate and ventricular pressure. J Pharmacol Exp Ther 1981;218:289–295.[Free Full Text]
  42. Chauncey DM Jr, Schelbert HR, Halpern SE, et al. Tissue distribution studies with radioactive manganese: a potential agent for myocardial imaging. J Nucl Med 1977;18:933–936.[Abstract/Free Full Text]
  43. Atkins HL, Som P, Fairchild RG, et al. Myocardial positron tomography with manganese-52m. Radiology 1979; 133(3):769–774.[Abstract]
  44. Buck A, Nguyen N, Burger C, et al. Quantitative evaluation of manganese-52m as a myocardial perfusion tracer in pigs using positron emission tomography. Eur J Nucl Med 1996;23:1619–1627.[CrossRef][Medline]
  45. Gorell JM, Johnson CC, Rybicki BA, et al. Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson's disease. Neurotoxicology 1999;20:239–247.[Medline]
  46. Mergler D, Baldwin M, Belanger S, et al. Manganese neurotoxicity, a continuum of dysfunction: results from a community based study. Neurotoxicology 1999;20:327–342.[Medline]
  47. Budinger TF. Nuclear magnetic resonance (NMR) in vivo studies: known thresholds for health effects. J Comput Assist Tomogr 1981;5:800–811.[Medline]
  48. Gaffey CT, Tenforde TS. Alterations in the rat electrocardiogram induced by stationary magnetic fields. Bioelectromagnetics 1981;2:357–370.[CrossRef][Medline]
  49. Sinusas AJ, Trautman KA, Bergin JD, et al. Quantification of area at risk during coronary occlusion and degree of myocardial salvage after reperfusion with technetium-99m methoxyisobutyl isonitrile. Circulation 1990;82:1424–1437.[Abstract/Free Full Text]
  50. Gibbons RJ, Verani MS, Behrenbeck T, et al. Feasibility of tomographic 99mTc-hexakis-2-methoxy-2-methylpropyl-isonitrile imaging for the assessment of myocardial area at risk and the effect of treatment in acute myocardial infarction. Circulation 1989;80:1277–1286.[Abstract/Free Full Text]
  51. Wagner A, Mahrholdt H, Holly TA, et al. Contrast-enhanced MRI and routine single photon emission computed tomography (SPECT) perfusion imaging for detection of subendocardial myocardial infarcts: an imaging study. Lancet 2003;361:374–379.[CrossRef][Medline]
  52. Gibbons RJ, Miller TD, Christian TF. Infarct size measured by single photon emission computed tomographic imaging with (99m)Tc-sestamibi: a measure of the efficacy of therapy in acute myocardial infarction. Circulation 2000;101:101–108.[Abstract/Free Full Text]
  53. Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation 1999;100:1992–2002.[Abstract/Free Full Text]
  54. Pennell DJ, Underwood R. Magnetic resonance imaging of the heart. Br J Hosp Med 1993; 49:90–95, 98–102.[Medline]
  55. Sierra-Galan LM, Ingkanisorn WP, Rhoads KL, Agyeman KO, Arai AE. Qualitative assessment of regional left ventricular function can predict MRI or radionuclide ejection fraction: an objective alternative to eyeball estimates. J Cardiovasc Magn Reson 2003;5:451–463.[CrossRef][Medline]
  56. Nagel E, al-Saadi N, Fleck E. Cardiovascular magnetic resonance: myocardial perfusion. Herz 2000;25:409–416.[CrossRef][Medline]




This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Natanzon, A.
Right arrow Articles by Arai, A. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Natanzon, A.
Right arrow Articles by Arai, A. E.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
RADIOLOGY RADIOGRAPHICS RSNA JOURNALS ONLINE