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MR Imaging of Reperfused Myocardial Infarction: Comparison of Necrosis-Specific and Intravascular Contrast Agents in a Cat Model¹

¹ From the Departments of Radiology (S.S.L., H.W.G., S.B.P., J.B.S., T.H.L.) and Diagnostic Pathology (G.G.), Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap-Dong, Songpa-Ku, Seoul 138-736, Korea; and Department of Radiology, Hanseo University, Seosan, Korea (C.H.L.). Received September 4, 2001; revision requested November 7; final revision received June 3, 2002; accepted July 16. Supported by a research grant (HMP-98-G-1-028) from the Korean Health and Welfare Ministry. Address correspondence to T.H.L. (e-mail: thlim@www.amc.seoul.kr).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To compare T2-weighted and Gadomer-17– and bis-gadolinium mesoporphyrins–enhanced magnetic resonance (MR) images for distinguishing reversibly from irreversibly damaged myocardium in a cat model of reperfused myocardial infarction.

MATERIALS AND METHODS: Twelve cats underwent 90 minutes of occlusion and 90 minutes of reperfusion of the left anterior descending coronary artery. After baseline T1- and T2-weighted MR images were obtained, Gadomer-17–enhanced and bis-gadolinium mesoporphyrins–enhanced T1-weighted images were sequentially obtained for 6 hours and 2 hours, respectively. After MR imaging, all cats were sacrificed for 2,3,5-triphenyltetrazolium chloride (TTC) histochemical tissue staining. Areas of abnormal signal intensity on T2-weighted and Gadomer-17–enhanced and bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images were compared with the areas of infarction seen at TTC histochemical staining by using repeated-measures two-way analysis of variance, linear regression analysis, and Bland-Altman analysis.

RESULTS: Mean areas of abnormally high signal intensity on T2-weighted and Gadomer-17–enhanced T1-weighted MR images (43.9% of the left ventricular surface area ± 11.9 [SD] and 37.7% ± 10.1, respectively) were significantly larger than the mean area of myocardial infarction at TTC staining (25.7% ± 12.5) (P < .001). However, there was excellent correlation between the size of an enhancing area on bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images and that of myocardial infarction at TTC staining (r = 0.916, P < .001).

CONCLUSION: bis-Gadolinium mesoporphyrins–enhanced T1-weighted MR images accurately reflect the area of infarction, whereas the size of infarction is overestimated on T2-weighted and Gadomer-17–enhanced T1-weighted MR images, which seem to depict the periinfarct area as well as the infarct area.

© RSNA, 2003

Index terms: Animals • Contrast media, experimental studies • Magnetic resonance (MR), contrast media • Myocardium, infarction, 511.771 • Myocardium, MR, 511.12143

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Because reperfusion after acute myocardial infarction often results in regions of contractile dysfunction that may ultimately recover, accurate discrimination between reversibly damaged and irreversibly damaged myocardium in the early period after infarction is important for further therapeutic decision making (1,2). Recently, magnetic resonance (MR) imaging, a noninvasive imaging technique, has been extensively investigated because of its ability to provide high spatial resolution and excellent tissue contrast in the evaluation of patients with acute myocardial infarction. Various kinds of contrast materials have been used for MR imaging of myocardial infarction in both research and clinical settings and have been shown to have the potential to enable differentiation of ischemic from normal myocardium (3–5) and irreversibly damaged from reversibly damaged myocardium (4,6–9).

Intravascular contrast agents have been investigated for their several advantages over extracellular contrast agents. Unlike the latter agents, which rapidly equilibrate between the intravascular and interstitial space after intravenous administration, the former agents have a longer intravascular half-life and a reduced diffusion rate through the endothelial wall of intact blood vessels (10). Therefore, the use of intravascular contrast agents results in a longer acquisition time window of differential enhancement between ischemic and normal myocardium during the first pass; these agents also permit accurate quantification of both tissue blood volume and perfusion (11–13).

A new synthetic blood pool contrast agent, Gadomer-17 (Schering, Berlin, Germany), which has a molecular weight of 17,453 d, is a gadolinium-based contrast agent of intermediate molecular size. It acts like an intravascular contrast agent during the first pass and is rapidly eliminated by glomerular filtration within 24 hours (10–12). These qualities make it promising for use as an intravascular contrast agent. Results of several animal studies have demonstrated the advantages of using this contrast agent versus extracellular contrast agents in MR angiography and the assessment of myocardial perfusion (14,15). However, to our knowledge, the enhancement pattern of Gadomer-17 in a setting of acute reperfused myocardial infarction has not yet been evaluated.

Bis-gadolinium mesoporphyrins (Gadophrin-2; Schering), a contrast agent that has a molecular weight of 1,697 d, was originally developed as a tumor-specific contrast agent for use in MR imaging. It has been shown that bis-gadolinium mesoporphyrins has affinity for only necrotic tissues (16). In a previous study (4), we demonstrated that enhancement of MR images with this agent enabled delineation of irreversibly damaged from reversibly damaged myocardium and accurate sizing of irreversibly damaged myocardium because, after administration of this agent, reperfused myocardial infarction shows strong and persistent enhancement.

The purpose of our study was to compare T2-weighted and Gadomer-17– and bis-gadolinium mesoporphyrins–enhanced MR imaging for distinguishing reversibly damaged from irreversibly damaged myocardium in a cat model of reperfused myocardial infarction.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Animal Preparation
This study was approved by the committee on animal research of the Asan Medical Center of the University of Ulsan College of Medicine. Twelve adult cats weighing from 3.5–5.1 kg (mean weight, 4.4 kg) were intubated and then anesthetized with 5% halothane. Blood pressure and heart rate were recorded on a cardiac monitor through a cannula inserted into the femoral artery. An intravenous line was placed in the femoral vein for administration of drugs and contrast materials.

Each cat underwent mechanical ventilation while a left lateral thoracotomy was performed along the fifth intercostal space. Pericardiotomy was performed by means of a midline incision, and a pericardial cradle was prepared by attaching the margins of the dissected pericardium to the adjacent thoracic wall. The left anterior descending (LAD) coronary artery was isolated distal to the first diagonal branch, and a snare loop was made with 4-0 silk placed in a slender plastic tube. Occlusion of the LAD coronary artery was produced by simply fastening the snare loop. The appearance of cyanosis in the area of the myocardium at risk was used to confirm successful coronary artery occlusion. Reperfusion of the LAD coronary artery was produced by releasing the snare loop. The cats underwent 90 minutes of occlusion of the LAD coronary artery followed by 90 minutes of reperfusion.

MR Imaging and Contrast Agent Administration
MR imaging was performed with a 1.5-T MR imaging unit (Magnetom Vision; Siemens Medical System, Erlangen, Germany) and a 27-cm-diameter circularly polarized head array coil. Stable anesthesia was maintained during the entire course of the experiment; blood pressure and pulse rate were also monitored. Heart rates were maintained at 140–170 beats per minute during MR imaging. After 90 minutes of reperfusion and before contrast material injection, electrocardiographically triggered breath-hold turbo spin-echo T2-weighted MR images and electrocardiography-triggered turbo spin-echo T1-weighted MR images were obtained along the short axis of the heart. Because all cats underwent mechanical ventilation during the examination, a breath-hold state could easily be achieved by stopping mechanical ventilation during image acquisition.

The acquisition parameters for T2-weighted MR imaging were as follows: repetition time msec/echo time msec, 1,300–1,500/82 (repetition time was varied according to heart rate); echo train length, 33; acquisition time, 9–10 seconds; matrix size, 132 x 256; field of view, 210 x 280 mm; section thickness, 5 mm; and no gap. The acquisition parameters for T1-weighted MR imaging were as follows: 600–900/25 (repetition time was varied according to heart rate); one signal acquired; field of view, 210 x 280 mm; section thickness, 5 mm; and no gap. All images were obtained along the short axis of the heart; images in the sagittal plane were also occasionally acquired to provide additional information about the status of the myocardium.

Gadomer-17 and bis-gadolinium mesoporphyrins were each injected via the femoral vein at doses of 0.05 mmol per kilogram of body weight and 0.025 mmol/kg, respectively. The methods of synthesis and the chemical structures, physiochemical properties, and imaging behaviors of Gadomer-17 and bis-gadolinium mesoporphyrins have previously been described in detail (12,17). After baseline MR images were obtained, Gadomer-17 was administered. Because the enhancement pattern of reperfused myocardial infarction in Gadomer-17–enhanced MR imaging has not been established previously, Gadomer-17–enhanced T1-weighted MR images were obtained for 6 hours in all 12 cats so that the enhancement pattern could be determined. A series of MR images were obtained at 10-minute intervals for the 1st hour, at 30-minute intervals between hours 1 and 3, and at 1-hour intervals between hours 3 and 6.

After completion of Gadomer-17–enhanced T1-weighted MR imaging, bis-gadolinium mesoporphyrins was administered. Because we had observed in our previous study (4) that peak enhancement was detected from 1–3 hours after contrast agent injection at bis-gadolinium mesoporphyrins–enhanced MR imaging and that there was no significant change in the size of the enhancing area from 40 minutes to 12 hours after contrast agent administration, bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images were obtained at 30-minute intervals for only 2 hours in all 12 cats.

Postmortem Histochemical Staining
After MR imaging, all animals were sacrificed by means of injection of potassium chloride solution. The heart was removed and cut into five or six 5-mm-thick consecutive slices in the same transverse planes in which the MR images had been obtained. The specimens were immersed in a 1.5% 2,3,5-triphenyltetrazolium chloride (TTC) solution at 36°C and stained for 15 minutes. The specimens were then stored in a 10% buffered formalin solution for 12 hours. The area of infarction was defined as the area that did not show TTC staining, and the noninfarcted myocardium was defined as the area that did show TTC staining. Photographs of the TTC-stained specimens were scanned into a computer (Macintosh; Apple Computers, Cupertino, Calif) so that the sizes of the areas of infarction and the left ventricle could be measured by using public domain image processing software (IMAGE 135; National Institutes of Health, Bethesda, Md).

Image Analysis
All MR images were analyzed by two experienced radiologists (S.S.L., T.H.L.) who worked independently; discrepancies were resolved in consensus. On Gadomer-17–enhanced T1-weighted MR images, signal intensities were measured in regions of interest located in enhancing and nonenhancing areas. The contrast ratio was calculated as the signal intensity in the enhanced area divided by that in the nonenhanced area. The changes in signal intensity were plotted versus time. We measured the size of the area of abnormal signal intensity on the monitor of the MR imaging unit by using the software of the 1.5-T Magnetom Vision system. The observers manually traced the entire myocardium of the left ventricle, the high-signal-intensity area on T2-weighted MR images, the enhancing area on Gadomer-17–enhanced T1-weighted MR images, and the enhancing area on the bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images.

On Gadomer-17–enhanced T1-weighted MR images, the size of the enhancing area was measured at each time point during the observation period. On bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images, the size of the enhancing area was measured on images obtained 90 or 120 minutes after contrast material administration. All measurements on MR images were repeated twice, and the mean value was used to calculate the size of the area of abnormal signal intensity. The size of the area of abnormal signal intensity on MR images and that of infarcted myocardium at TTC staining were expressed as a percentage of the size of the entire left ventricle.

Statistical Analysis
A repeated-measures two-way analysis of variation was used to determine the differences in the sizes of the enhancing areas on Gadomer-17–enhanced T1-weighted MR images over time during the observation period. For comparison of these images with other MR images and TTC staining results, the mean size of the enhancing area at the time of peak enhancement (20–40 minutes) was used. For bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images, the size of the enhancing area was recorded 90 minutes and 120 minutes after contrast material administration; the mean of these two measurements was used for comparison with size on other MR images because in our previous study (4), peak enhancement was detected from 1 to 3 hours after contrast material injection and there was no significant change in the size of the enhancing area from 40 minutes to 12 hours after contrast material administration.

The size of each area of infarction at TTC staining and the size of each area of abnormally high signal intensity on T2-weighted MR images, Gadomer-17–enhanced T1-weighted MR images, and bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images were compared. The significance of the differences was determined by using the repeated-measures two-way analysis of variance. The least significant difference test was then performed so that we could determine the differences between the MR imaging results and the TTC staining results. Linear regression analysis and Bland-Altman analysis were used to determine the agreement between the size of the area of abnormally high signal intensity on each MR image and that of myocardial infarction at TTC staining. According to the Bland-Altman method (18), the limits of agreement are given as means ± SDs, where the mean value is the average of the differences in the data. We considered statistically significant differences to be present when the P value was less than .05.

Ultrastructural Examinations with Electron Microscopy
Electron microscopic examinations were performed in 10 of 12 cases. In the remaining two cases, electron microscopic examination was not possible due to the presence in the samples of abundant artifacts, which resulted from faulty preparation of the samples. A representative slice of the specimen was processed for the ultrastructural examination. Tissue from the center of the infarction (ie, the infarct center) was removed from the center of the area that did not show TTC staining. For the periinfarct area, three tissue samples (representing periinfarct zones 1, 2, and 3) were sampled from the peripheral region that showed TTC staining 2 mm, 4 mm, and 6 mm lateral, respectively, from the region that did not show TTC staining.

Tissue was cut into 1-mm cubes and fixed in a 2.5% buffered glutaraldehyde solution for 12–16 hours; it was then additionally fixed in a solution of osmotic acid at 5°C for 2 hours. The cubes were then dehydrated in graded alcohol at room temperature and bathed in propylene oxide and Epon 812 (Polyscience, Niles, Ill) for 12–16 hours before being embedded in the latter. Slices of approximately 0.5 µm in thickness were cut with a diamond knife (LKB Ultramicrotome; Pharmacia, Uppsala, Sweden). Thin slices were mounted on a copper grid and stained with 4% aqueous uranyl acetate and lead citrate for examination with a transmission electron microscope (JEM-1200 EX II; Jeol, Tokyo, Japan). All electron microscopic examinations were performed by one experienced pathologist (G.G.) who also analyzed the results of these examinations.

The electron microscopic criteria used for distinguishing between irreversibly and reversibly damaged myocardium have been described previously (19). Ultrastructural findings of irreversibly damaged myocardium included electron-dense deposits in the mitochondrial matrix, disruption of the sarcolemma, and contraction band necrosis. Ultrastructural findings of reversibly damaged myocardium included mild edematous change, increased sarcoplasmic space, prominent I band, and mild peripheral aggregation of nuclear chromatin without any ultrastructural features of irreversibly damaged myocardium.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Nonenhanced T2-weighted MR Imaging Results versus TTC Staining Results
The mean size of the areas of abnormally high signal intensity on nonenhanced T2-weighted MR images was 43.9% ± 11.9 of the left ventricular surface area (Fig 1). The mean size of the areas of abnormally high signal intensity on T2-weighted MR images was significantly larger than that of the myocardial infarction measured at TTC staining (25.7% ± 12.5, P < .001). The limit of agreement calculated by using the method of Bland and Altman was 18.1% ± 7.6 (Fig 2).

View larger version (153K): [in this window] [in a new window] [Download PPT slide]   Figure 1a. MR images of the short axis of a cat heart at the midventricular level and the corresponding TTC-stained slice of reperfused myocardium. (a) Electrocardiographically-triggered turbo spin-echo T2-weighted MR image (1,400/82; echo train length, 33; matrix, 132 x 256; section thickness, 5 mm; no gap) shows the area of high signal intensity (arrows) in the territory of the LAD coronary artery. The mean size of the areas of abnormally high signal intensity on T2-weighted MR images was 45.3% of the left ventricular surface area. (b) Gadomer-17- and (c) bis-gadolinium mesoporphyrins-enhanced electrocardiographically-triggered turbo spin-echo T1-weighted MR images (700/25; matrix, 132 x 256; section thickness, 5 mm; no gap) also show increased signal intensity (arrows) in the territory of the LAD coronary artery. The mean sizes of the enhancing areas on Gadomer-17- and bis-gadolinium mesoporphyrins-enhanced T1-weighted MR images were 40.2% and 29.7% of the left ventricular surface area, respectively. In contrast to the transmural enhancement pattern seen on the Gadomer-17-enhanced T1-weighted MR image in b, the bis-gadolinium mesoporphyrins-enhanced T1-weighted MR image in c clearly depicts subendocardial infarction. (d) Macroscopic photograph of a TTC-stained myocardial specimen obtained at the same level as the MR images. The area of infarction corresponds to the nonstained area (*) seen in the territory of the LAD coronary artery. The mean size of infarcted myocardium at TTC staining was 28.5% of the left ventricular surface area. In this case, myocardial infarction was overestimated on the T2-weighted MR image in a and on the Gadomer-17-enhanced T1-weighted MR image in b by 16.8% and 11.7%, respectively. In contrast, the size of the enhancing area on the bis-gadolinium mesoporphyrins-enhanced T1-weighted MR image in c is nearly identical to the size of myocardial infarction at TTC staining in d.

View larger version (147K): [in this window] [in a new window] [Download PPT slide]   Figure 1b. MR images of the short axis of a cat heart at the midventricular level and the corresponding TTC-stained slice of reperfused myocardium. (a) Electrocardiographically-triggered turbo spin-echo T2-weighted MR image (1,400/82; echo train length, 33; matrix, 132 x 256; section thickness, 5 mm; no gap) shows the area of high signal intensity (arrows) in the territory of the LAD coronary artery. The mean size of the areas of abnormally high signal intensity on T2-weighted MR images was 45.3% of the left ventricular surface area. (b) Gadomer-17- and (c) bis-gadolinium mesoporphyrins-enhanced electrocardiographically-triggered turbo spin-echo T1-weighted MR images (700/25; matrix, 132 x 256; section thickness, 5 mm; no gap) also show increased signal intensity (arrows) in the territory of the LAD coronary artery. The mean sizes of the enhancing areas on Gadomer-17- and bis-gadolinium mesoporphyrins-enhanced T1-weighted MR images were 40.2% and 29.7% of the left ventricular surface area, respectively. In contrast to the transmural enhancement pattern seen on the Gadomer-17-enhanced T1-weighted MR image in b, the bis-gadolinium mesoporphyrins-enhanced T1-weighted MR image in c clearly depicts subendocardial infarction. (d) Macroscopic photograph of a TTC-stained myocardial specimen obtained at the same level as the MR images. The area of infarction corresponds to the nonstained area (*) seen in the territory of the LAD coronary artery. The mean size of infarcted myocardium at TTC staining was 28.5% of the left ventricular surface area. In this case, myocardial infarction was overestimated on the T2-weighted MR image in a and on the Gadomer-17-enhanced T1-weighted MR image in b by 16.8% and 11.7%, respectively. In contrast, the size of the enhancing area on the bis-gadolinium mesoporphyrins-enhanced T1-weighted MR image in c is nearly identical to the size of myocardial infarction at TTC staining in d.

View larger version (118K): [in this window] [in a new window] [Download PPT slide]   Figure 1c. MR images of the short axis of a cat heart at the midventricular level and the corresponding TTC-stained slice of reperfused myocardium. (a) Electrocardiographically-triggered turbo spin-echo T2-weighted MR image (1,400/82; echo train length, 33; matrix, 132 x 256; section thickness, 5 mm; no gap) shows the area of high signal intensity (arrows) in the territory of the LAD coronary artery. The mean size of the areas of abnormally high signal intensity on T2-weighted MR images was 45.3% of the left ventricular surface area. (b) Gadomer-17- and (c) bis-gadolinium mesoporphyrins-enhanced electrocardiographically-triggered turbo spin-echo T1-weighted MR images (700/25; matrix, 132 x 256; section thickness, 5 mm; no gap) also show increased signal intensity (arrows) in the territory of the LAD coronary artery. The mean sizes of the enhancing areas on Gadomer-17- and bis-gadolinium mesoporphyrins-enhanced T1-weighted MR images were 40.2% and 29.7% of the left ventricular surface area, respectively. In contrast to the transmural enhancement pattern seen on the Gadomer-17-enhanced T1-weighted MR image in b, the bis-gadolinium mesoporphyrins-enhanced T1-weighted MR image in c clearly depicts subendocardial infarction. (d) Macroscopic photograph of a TTC-stained myocardial specimen obtained at the same level as the MR images. The area of infarction corresponds to the nonstained area (*) seen in the territory of the LAD coronary artery. The mean size of infarcted myocardium at TTC staining was 28.5% of the left ventricular surface area. In this case, myocardial infarction was overestimated on the T2-weighted MR image in a and on the Gadomer-17-enhanced T1-weighted MR image in b by 16.8% and 11.7%, respectively. In contrast, the size of the enhancing area on the bis-gadolinium mesoporphyrins-enhanced T1-weighted MR image in c is nearly identical to the size of myocardial infarction at TTC staining in d.

View larger version (197K): [in this window] [in a new window] [Download PPT slide]   Figure 1d. MR images of the short axis of a cat heart at the midventricular level and the corresponding TTC-stained slice of reperfused myocardium. (a) Electrocardiographically-triggered turbo spin-echo T2-weighted MR image (1,400/82; echo train length, 33; matrix, 132 x 256; section thickness, 5 mm; no gap) shows the area of high signal intensity (arrows) in the territory of the LAD coronary artery. The mean size of the areas of abnormally high signal intensity on T2-weighted MR images was 45.3% of the left ventricular surface area. (b) Gadomer-17- and (c) bis-gadolinium mesoporphyrins-enhanced electrocardiographically-triggered turbo spin-echo T1-weighted MR images (700/25; matrix, 132 x 256; section thickness, 5 mm; no gap) also show increased signal intensity (arrows) in the territory of the LAD coronary artery. The mean sizes of the enhancing areas on Gadomer-17- and bis-gadolinium mesoporphyrins-enhanced T1-weighted MR images were 40.2% and 29.7% of the left ventricular surface area, respectively. In contrast to the transmural enhancement pattern seen on the Gadomer-17-enhanced T1-weighted MR image in b, the bis-gadolinium mesoporphyrins-enhanced T1-weighted MR image in c clearly depicts subendocardial infarction. (d) Macroscopic photograph of a TTC-stained myocardial specimen obtained at the same level as the MR images. The area of infarction corresponds to the nonstained area (*) seen in the territory of the LAD coronary artery. The mean size of infarcted myocardium at TTC staining was 28.5% of the left ventricular surface area. In this case, myocardial infarction was overestimated on the T2-weighted MR image in a and on the Gadomer-17-enhanced T1-weighted MR image in b by 16.8% and 11.7%, respectively. In contrast, the size of the enhancing area on the bis-gadolinium mesoporphyrins-enhanced T1-weighted MR image in c is nearly identical to the size of myocardial infarction at TTC staining in d.

View larger version (27K): [in this window] [in a new window] [Download PPT slide]   Figure 2a. Bland-Altman plots display average of surface area of infarcted myocardium at TTC staining and area of abnormally high signal intensity on MR images (x axes) versus the difference between them (y axes). The limits of agreement were (a) 18.1% ± 7.6 for nonenhanced T2-weighted MR imaging and TTC staining, (b) 12.0 ± 6.9 for Gadomer-17-enhanced MR imaging and TTC staining, and (c) 1.5% ± 5.1 for bis-gadolinium mesoporphyrins-enhanced MR imaging and TTC staining. The difference in the infarction size depicted at bis-gadolinium mesoporphyrins-enhanced MR imaging and that depicted at TTC staining showed close agreement, and Bland-Altman analysis disclosed no significant degree of systematic measurement bias.

View larger version (28K): [in this window] [in a new window] [Download PPT slide]   Figure 2b. Bland-Altman plots display average of surface area of infarcted myocardium at TTC staining and area of abnormally high signal intensity on MR images (x axes) versus the difference between them (y axes). The limits of agreement were (a) 18.1% ± 7.6 for nonenhanced T2-weighted MR imaging and TTC staining, (b) 12.0 ± 6.9 for Gadomer-17-enhanced MR imaging and TTC staining, and (c) 1.5% ± 5.1 for bis-gadolinium mesoporphyrins-enhanced MR imaging and TTC staining. The difference in the infarction size depicted at bis-gadolinium mesoporphyrins-enhanced MR imaging and that depicted at TTC staining showed close agreement, and Bland-Altman analysis disclosed no significant degree of systematic measurement bias.

View larger version (31K): [in this window] [in a new window] [Download PPT slide]   Figure 2c. Bland-Altman plots display average of surface area of infarcted myocardium at TTC staining and area of abnormally high signal intensity on MR images (x axes) versus the difference between them (y axes). The limits of agreement were (a) 18.1% ± 7.6 for nonenhanced T2-weighted MR imaging and TTC staining, (b) 12.0 ± 6.9 for Gadomer-17-enhanced MR imaging and TTC staining, and (c) 1.5% ± 5.1 for bis-gadolinium mesoporphyrins-enhanced MR imaging and TTC staining. The difference in the infarction size depicted at bis-gadolinium mesoporphyrins-enhanced MR imaging and that depicted at TTC staining showed close agreement, and Bland-Altman analysis disclosed no significant degree of systematic measurement bias.

View larger version (27K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Line graph depicts the time course of signal intensity enhancement after administration of 0.05 mmol/kg Gadomer-17. Signal intensity of the enhancing area increased rapidly from the time immediately following contrast material injection to 40 minutes after. Maximum enhancement was detected from 10-40 minutes after contrast material administration (mean enhancement, 167% ± 14.8 of normal myocardium). After reaching maximum enhancement, the signal intensity of the area decreased gradually and returned to the precontrast state 5 hours after contrast material injection.

Gadomer-17–enhanced T1-weighted MR Imaging Results versus TTC Staining Results
The mean size of the enhancing areas on Gadomer-17–enhanced T1-weighted MR images (37.7% ± 10.1) was significantly larger than the areas of infarction measured at TTC staining (P < .001) (Fig 1). Although a linear relationship was present between the sizes of the enhancing areas measured on Gadomer-17–enhanced T1-weighted MR images and those of myocardial infarction measured at TTC staining (r = 0.836, P < .001), results of Bland-Altman analysis showed no agreement in the mean difference in the infarction sizes between the two measurements. The limit of agreement calculated by using the method of Bland and Altman was 12.0% ± 6.9 (Fig 2).

bis-Gadolinium Mesoporphyrins–enhanced T1-weighted MR Imaging Results versus TTC Staining Results
The mean size of the enhancing areas on bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images was 27.3% ± 10.5 (Fig 1). There was excellent correlation between the size of the enhancing areas measured on bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images and that of myocardial infarction measured at TTC staining (r = 0.916, P < .001). The limit of agreement calculated by using the method of Bland and Altman was 1.5% ± 5.1, and no significant degree of systematic measurement bias was present (Fig 2).

Comparison of MR Images
The mean size of the areas of abnormally high signal intensity on T2-weighted MR images was significantly larger than that of the enhancing areas on Gadomer-17–enhanced T1-weighted MR images (P < .05) and on bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images (P < .001) (Fig 4). A statistically significant difference was also present between the mean size of the enhancing areas on Gadomer-17–enhanced T1-weighted MR images and that of the enhancing areas on bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images (P < .001).

View larger version (23K): [in this window] [in a new window] [Download PPT slide]   Figure 4. Bar graph illustrates the measured sizes of the high-signal-intensity areas on T2-weighted MR images (T2), the enhancing areas on Gadomer-17-enhanced T1-weighted MR images, the enhancing areas on bis-gadolinium mesoporphyrins-enhanced T1-weighted MR images (Gadophrin-2), and the areas of infarction seen at TTC staining. The high-signal-intensity areas on T2-weighted MR images were larger than the enhancing areas on Gadomer-17-enhanced T1-weighted MR images and bis-gadolinium mesoporphyrins-enhanced T1-weighted MR images. The enhancing areas seen on Gadomer-17-enhanced T1-weighted MR images were larger than the enhancing areas seen on bis-gadolinium mesoporphyrins-enhanced T1-weighted MR images and the areas of myocardial infarction seen at TTC staining.

View larger version (162K): [in this window] [in a new window] [Download PPT slide]   Figure 5a. Photomicrographs show the ultrastructural features of cat myocardium after 90 minutes of ischemia followed by 90 minutes of reperfusion. (a) Ultrastructures of the infarct center. The mitochondria are swollen and contain electron-opaque, granular dense bodies (black arrows). Contraction bands (white arrows) are present. (TTC stain; original magnification, x4,000.) (b) Ultrastructures of periinfarct zone 1 (2 mm lateral from the margin of the infarct area) show interfibrous edema and prominent I bands (arrowheads). These findings are consistent with ultrastructural findings of reversibly damaged myocardium. However, some areas show swollen mitochondria and contraction bands (arrows), which represent ultrastructural changes of irreversibly damaged myocardium. (TTC stain; original magnification, x4,000.) (c) Ultrastructures of periinfarct zone 2 (4 mm lateral from the margin of the infarct area) show interfibrous edema and prominent I bands (arrows). Although the sarcoplasmic space has increased, the plasmalemma (arrowheads) of the sarcolemma is intact. These findings are consistent with the ultrastructural changes of irreversibly damaged myocardium. (TTC stain; original magnification, x4,000.) (d) Ultrastructures of periinfarct zone 3 (6 mm lateral from the margin of the infarct area). Myocardial cells are surrounded by an intact sarcolemma (arrowheads). Mitochondria (*) are abundant and I bands (arrows) appear normal. These findings are consistent with the ultrastructural changes of normal myocardium. (TTC stain; original magnification, x4,000.)

View larger version (147K): [in this window] [in a new window] [Download PPT slide]   Figure 5b. Photomicrographs show the ultrastructural features of cat myocardium after 90 minutes of ischemia followed by 90 minutes of reperfusion. (a) Ultrastructures of the infarct center. The mitochondria are swollen and contain electron-opaque, granular dense bodies (black arrows). Contraction bands (white arrows) are present. (TTC stain; original magnification, x4,000.) (b) Ultrastructures of periinfarct zone 1 (2 mm lateral from the margin of the infarct area) show interfibrous edema and prominent I bands (arrowheads). These findings are consistent with ultrastructural findings of reversibly damaged myocardium. However, some areas show swollen mitochondria and contraction bands (arrows), which represent ultrastructural changes of irreversibly damaged myocardium. (TTC stain; original magnification, x4,000.) (c) Ultrastructures of periinfarct zone 2 (4 mm lateral from the margin of the infarct area) show interfibrous edema and prominent I bands (arrows). Although the sarcoplasmic space has increased, the plasmalemma (arrowheads) of the sarcolemma is intact. These findings are consistent with the ultrastructural changes of irreversibly damaged myocardium. (TTC stain; original magnification, x4,000.) (d) Ultrastructures of periinfarct zone 3 (6 mm lateral from the margin of the infarct area). Myocardial cells are surrounded by an intact sarcolemma (arrowheads). Mitochondria (*) are abundant and I bands (arrows) appear normal. These findings are consistent with the ultrastructural changes of normal myocardium. (TTC stain; original magnification, x4,000.)

View larger version (167K): [in this window] [in a new window] [Download PPT slide]   Figure 5c. Photomicrographs show the ultrastructural features of cat myocardium after 90 minutes of ischemia followed by 90 minutes of reperfusion. (a) Ultrastructures of the infarct center. The mitochondria are swollen and contain electron-opaque, granular dense bodies (black arrows). Contraction bands (white arrows) are present. (TTC stain; original magnification, x4,000.) (b) Ultrastructures of periinfarct zone 1 (2 mm lateral from the margin of the infarct area) show interfibrous edema and prominent I bands (arrowheads). These findings are consistent with ultrastructural findings of reversibly damaged myocardium. However, some areas show swollen mitochondria and contraction bands (arrows), which represent ultrastructural changes of irreversibly damaged myocardium. (TTC stain; original magnification, x4,000.) (c) Ultrastructures of periinfarct zone 2 (4 mm lateral from the margin of the infarct area) show interfibrous edema and prominent I bands (arrows). Although the sarcoplasmic space has increased, the plasmalemma (arrowheads) of the sarcolemma is intact. These findings are consistent with the ultrastructural changes of irreversibly damaged myocardium. (TTC stain; original magnification, x4,000.) (d) Ultrastructures of periinfarct zone 3 (6 mm lateral from the margin of the infarct area). Myocardial cells are surrounded by an intact sarcolemma (arrowheads). Mitochondria (*) are abundant and I bands (arrows) appear normal. These findings are consistent with the ultrastructural changes of normal myocardium. (TTC stain; original magnification, x4,000.)

View larger version (158K): [in this window] [in a new window] [Download PPT slide]   Figure 5d. Photomicrographs show the ultrastructural features of cat myocardium after 90 minutes of ischemia followed by 90 minutes of reperfusion. (a) Ultrastructures of the infarct center. The mitochondria are swollen and contain electron-opaque, granular dense bodies (black arrows). Contraction bands (white arrows) are present. (TTC stain; original magnification, x4,000.) (b) Ultrastructures of periinfarct zone 1 (2 mm lateral from the margin of the infarct area) show interfibrous edema and prominent I bands (arrowheads). These findings are consistent with ultrastructural findings of reversibly damaged myocardium. However, some areas show swollen mitochondria and contraction bands (arrows), which represent ultrastructural changes of irreversibly damaged myocardium. (TTC stain; original magnification, x4,000.) (c) Ultrastructures of periinfarct zone 2 (4 mm lateral from the margin of the infarct area) show interfibrous edema and prominent I bands (arrows). Although the sarcoplasmic space has increased, the plasmalemma (arrowheads) of the sarcolemma is intact. These findings are consistent with the ultrastructural changes of irreversibly damaged myocardium. (TTC stain; original magnification, x4,000.) (d) Ultrastructures of periinfarct zone 3 (6 mm lateral from the margin of the infarct area). Myocardial cells are surrounded by an intact sarcolemma (arrowheads). Mitochondria (*) are abundant and I bands (arrows) appear normal. These findings are consistent with the ultrastructural changes of normal myocardium. (TTC stain; original magnification, x4,000.)

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Gadomer-17 is a 24-gadolinium cascade polymer with a molecular weight of 17,453 d. It is the product of combining a trimesoyl triamide central core with 18 lysine amino acid residues to yield a 24-mer polyamine intermediate in which the free amine has subsequently been conjugated to 24 chelators. Because of the higher molecular weight of Gadomer-17, its T1 relaxivity is almost four times that of gadopentetate dimeglumine (12). Although the compound does not quickly diffuse into the extravascular space after intravenous administration due to its reduced diffusion rate through the endothelial wall of an intact blood vessel, it is excreted rapidly via glomerular filtration (10,12). Therefore, Gadomer-17 is a promising intravascular contrast agent that is not subject to prolonged body retention, which is the most serious limitation of other macromolecular intravascular contrast agents (20).

The usefulness of Gadomer-17 in MR angiography as well as in the quantification of myocardial perfusion has been confirmed by several groups of researchers with both animal and phantom models (12,14,15,20). For a complete evaluation of myocardial infarction, assessment of the delayed enhancement pattern is important for determining whether the damage to the myocardium is reversible. However, to our knowledge, the enhancement pattern of this contrast agent in acute reperfused myocardial infarction had not been evaluated.

The principal findings of this study are as follows: (a) Infarcted myocardium exhibits transient enhancement on Gadomer-17–enhanced T1-weighted MR images. Maximum enhancement was detected from 10 to 40 minutes following contrast administration. (b) The size of acute myocardial infarction was overestimated on T2-weighted and Gadomer-17–enhanced MR images, whereas the size of the enhancing area on bis-gadolinium mesoporphyrins–enhanced MR images matched that of myocardial infarction at TTC staining. (c) Electron microscopic examination of infarct centers revealed ultrastructural findings of irreversibly damaged myocardium. Although the ultrastructural findings in periinfarct areas varied, the principal finding was reversibly damaged myocardium. Therefore, MR imaging enhanced with bis-gadolinium mesoporphyrins precisely depicts irreversibly damaged myocardium, whereas the area of high signal intensity on T2-weighted MR images and the enhancing area on Gadomer-17–enhanced T1-weighted MR images seem to include periinfarct areas as well as infarct areas.

The results of this study are consistent with those of previous studies in which other intravascular contrast agents were used; the results of those studies demonstrated that the sizes of areas enhanced with the use of other contrast agents were larger than those of areas of infarction at TTC histochemical staining (3,21–23). The results of previous studies in which bis-gadolinium mesoporphyrins was used (4,7) also revealed that the sizes of enhancing areas at bis-gadolinium mesoporphyrins–enhanced MR imaging matched well those of myocardial infarction at TTC staining.

To our knowledge, the mechanism of signal intensity enhancement with Gadomer-17 in reperfused myocardial infarction has not been documented. However, results of previous studies with the intravascular contrast agents gadolinium diethylenetriaminepentaacetic acid (DTPA)– polylysine and Gd-DTPA–albumin demonstrated that enhancement of areas of infarction and periinfarction is attributable to microvascular hyperpermeability (24,25). Lim et al (24), in a study that involved the use of Gd-DTPA–polylysine and poly-L-lysine-fluorescein isothiocyanate as a fluorescent tracer molecule for the contrast agent, demonstrated that periinfarct areas show numerous interstitial distributions of fluorescence activity. Lim et al (24) theorized that microvascular hyperpermeability permits extravasation of macromolecular MR contrast agents and that the delayed clearance of extravasated contrast agent from an interstitial space might cause signal intensity enhancement in a periinfarct area.

Because Gadomer-17 is also an intravascular contrast agent, its mechanism of action seems to be similar to that of other intravascular contrast agents. Therefore, increased microvascular permeability may be the principal mechanism for enhancement of myocardial infarction and periinfarct areas. Another possible explanation for contrast enhancement of a periinfarct area may be the presence of reactive hyperemia occurring in the periphery of the infarction. During ischemia, blood vessels distal to the occlusion, as well as collateral vessels, dilate maximally in response to the release of vasodilators such as kinin, arachnoic acid, lactate, and adenosine (26,27). Thus, reactive hyperemia occurring after ischemia and infarction may play a role in the enhancement of a periinfarct area.

Bis-gadolinium mesoporphyrins, a necrosis-avid contrast material, consists of mesoporphyrin linked to gadolinium. The results of our previous study (4) demonstrated that infarcted myocardium was accurately delineated with this contrast agent. Furthermore, our previous results also demonstrated that occluded infarcted myocardium did not show contrast enhancement and could not be distinguished from normal myocardium with this contrast agent (28). However, little is known about the mechanism of accumulation of this contrast agent in necrotic tissue. The binding of this contrast agent to the denatured tissue component is suggested as a possible mechanism. However, Hofmann et al (17) proposed that accumulation of bis-gadolinium mesoporphyrins in necrotic tissue is caused by its binding to plasma albumin and its subsequent slow extravasation because they found that the only binding site of this agent was interstitial albumin, not other proteins, lipids, or DNA in the periphery of the necrotic area. Further studies are needed to elucidate the mechanism of accumulation.

In the present study, the mean size of the high-signal-intensity area on T2-weighted MR images was larger than that of the enhancing area on Gadomer-17–enhanced T1-weighted MR images, while the enhancing area on Gadomer-17–enhanced T1-weighted MR images was larger than the enhancing area on bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images. These results may be explained by the histologic status of the periinfarct area as demonstrated at electron microscopy, which revealed the gradual change in cellular damage in the periinfarct zone from periinfarct zone 1 to periinfarct zone 3. In most cases, periinfarct zone 1 had ultrastructural features of reversibly damaged myocardium mixed with scattered areas of irreversibly damaged myocardium, whereas periinfarct zone 3 had reversibly damaged myocardium or normal myocardium. In all cases, the periinfarct area adjacent to the infarct area had the most severe morphologic evidence of cellular injury, whereas the morphologic evidence of cellular injury was less severe in the periinfarct area furthest from the infarct area.

The high-signal-intensity areas on T2-weighted MR images are largely due to the presence of edema (29,30), whereas the enhancing areas on Gadomer-17–enhanced T1-weighted MR images may be attributable to increased capillary permeability and hyperemia. Therefore, the high-signal-intensity area on a T2-weighted MR image may include all of the periinfarct area containing edema, but the enhancing area on a Gadomer-17–enhanced T1-weighted MR image may include a periinfarct area that has cellular damage severe enough that the microvascular permeability is increased. In contrast, bis-gadolinium mesoporphyrins is known as a necrosis-avid contrast material (4,7). Enhancing areas on bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images therefore probably represent irreversibly damaged myocardium.

In contrast to the results of the present study, the results of a study in dogs by Kim et al (6) indicated that the spatial extent of hyperenhancing regions on gadopentetate dimeglumine–enhanced MR images was the same as that of myocardial infarction at TTC staining. The results of the study of Kim et al (6) are entirely different from ours. These differences may be explained by the different properties and enhancement mechanisms of the two contrast agents, Gadomer-17 and gadopentetate dimeglumine. Unlike Gadomer-17, gadopentetate dimeglumine is an extracellular contrast agent. The mechanism of enhancement of myocardial infarction with this contrast agent involves increased contrast agent distribution volume as well as prolonged wash-in and wash-out time constants (8,31,32).

However, whether delayed hyperenhancement after injection of gadopentetate dimeglumine results in accurate delineation of myocardial infarction is still being researched: Results of some studies have shown that acute myocardial infarction is overestimated at gadopentetate dimeglumine–enhanced MR imaging by 10%–20% (30,31,33). Therefore, further studies are needed to confirm the importance of delayed hyperenhancement after injection of gadopentetate dimeglumine.

Recently, a segmented inversion-recovery fast low-angle shot (IR-FLASH) technique was successfully applied in MR imaging of myocardial infarction with an extracellular contrast agent (34). Although we used a turbo spin-echo pulse sequence in this study, the segmented IR-FLASH sequence seems to be a promising pulse sequence in the delineation of myocardial infarction and the measurement of its size because of the improved contrast between infarcted and normal myocardium seen with use of this sequence. Therefore, an investigation in which IR-FLASH and a necrosis-specific or intravascular contrast agent are used may be helpful in the evaluation of myocardial status in reperfused myocardial infarction.

Our study did have certain limitations. First, there was a difference in the reperfusion time between T2-weighted MR images, Gadomer-17–enhanced T1-weighted MR images, and bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images. According to Saeed et al (35), there is reduction in the size of the hyperenhancing region on gadopentetate dimeglumine–enhanced MR images during the interval between 1 and 24 hours of reperfusion. However, it is still unclear whether the reduction in the size of the hyperenhancing region on gadopentetate dimeglumine–enhanced MR images is due to a recovery of reversibly damaged myocardium or a reduction in the size of myocardial infarction. Furthermore, the results of our previous study (4) of bis-gadolinium mesoporphyrins–enhanced MR imaging demonstrated that there was no significant change in the size of the enhancing region from 40 minutes to 12 hours after reperfusion.

Therefore, we believe that the different reperfusion times we used when sampling the infarct size in the present study have little effect on the actual size of myocardial infarction in the early period of reperfused myocardial infarction and that the different sizes of areas of abnormally high signal intensity on T2-weighted MR images and Gadomer-17– and bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images are attributable to the different mechanisms of contrast enhancement described above rather than to the reduction of the actual size of the myocardial infarction.

Second, we could not estimate the extent of ischemic areas because we did not measure the sizes of the areas at risk. Therefore, we could not correlate the sizes of areas of abnormally high signal intensity on MR images with those of ischemic areas. Third, direct area-to-area correlation between electron microscopy and MR imaging was not possible because tissue sampling for electron microscopy was performed on the basis of results of TTC staining rather than MR imaging. Thus, we could demonstrate the histologic status of periinfarct areas at electron microscopy. However, the histologic status of areas of myocardium seen as areas with different signal intensity behaviors on T2-weighted MR images, Gadomer-17–enhanced T1-weighted MR images, and bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images could not be directly assessed. We believe that further MR imaging studies in which ex vivo specimens are used are needed so that accurate area-to-area correlations between MR imaging and histologic results can be performed.

In conclusion, bis-gadolinium mesoporphyrins–enhanced T1-weighted MR images accurately depict an area of infarction, whereas at T2-weighted MR imaging and Gadomer-17–enhanced T1-weighted MR imaging, the size of infarction is often overestimated and the resulting images seem to depict the periinfarct area as well as the infarct area.

Practical application: When Gadomer-17 is used as an intravascular contrast agent for coronary MR angiography or myocardial perfusion studies in patients with reperfused myocardial infarction, the delayed hyperenhancement pattern cannot enable discrimination of reversibly damaged from irreversibly damaged myocardium. However, use of the necrosis-specific contrast agent bis-gadolinium mesoporphyrins may yield additional information about the viability of the damaged myocardium.

	ACKNOWLEDGMENTS

 
We thank In Suk Lee, PhD, Department of Statistics, College of Natural Science, Kyungpook National University, Taegu, Korea, for his advice on the statistical analysis of the data and Bonnie Hami, MA, Department of Radiology, University Hospitals of Cleveland, Ohio, for her editorial assistance. We also thank Sang Tae Kim, BS, and Keun Ho Lim, BS, Laboratory of the Department of Nuclear Magnetic Resonance, Asan Institute for Life Science, Seoul, Korea, for their technical assistance in the preparation of the animal model.

	FOOTNOTES

 
Abbreviations: DTPA = diethylenetriaminepentaacetic acid, IR-FLASH = inversion-recovery fast low-angle shot, LAD = left anterior descending, TTC = 2,3,5-triphenyltetrazolium chloride

Author contributions: Guarantor of integrity of entire study, T.H.L.; study concepts, T.H.L.; study design, S.S.L., S.B.P., T.H.L.; literature research, S.S.L., S.B.P.; experimental studies, C.H.L., G.Y.G.; data acquisition, S.S.L., H.W.G., J.B.S.; data analysis/interpretation, S.S.L., T.H.L.; statistical analysis, S.S.L.; manuscript preparation, S.S.L., H.W.G.; manuscript definition of intellectual content and editing, S.S.L., H.W.G., J.B.S., T.H.L.; manuscript revision/review and final version approval, all authors.

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