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(Radiology. 1999;213:247-257.)
© RSNA, 1999

Experimental Studies

Reperfused Myocardial Infarction as Seen with Use of Necrosis-specific versus Standard Extracellular MR Contrast Media in Rats1

Maythem Saeed, DVM, PhD, Jens Bremerich, MD, Michael F. Wendland, PhD, Rolf Wyttenbach, MD, Hanns-Joachim Weinmann, PhD and Charles B. Higgins, MD

1 From the Department of Radiology, University of California San Francisco, 505 Parnassus Ave, Box 0628, L308, San Francisco, CA 94143-0628 (M.S., J.B., M.F.W., R.W., C.B.H.), and Schering, Berlin, Germany (H.J.W.). From the 1998 RSNA scientific assembly. Received August 7, 1998; revision requested October 5; revision received November 6; accepted March 29, 1999. Address reprint requests to M.S. (e-mail: Maythem .Saeed@radiology.ucsf.edu).


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To measure the difference in size of reperfused myocardial infarction with necrosis-specific (bis-gadolinium-mesoporphyrin [hereafter, mesoporphyrin]) and standard extracellular (gadopentetate dimeglumine) magnetic resonance (MR) contrast media.

MATERIALS AND METHODS: Echo-planar (for T1 measurement) and spin-echo (for infarction size) MR imaging were conducted in 32 rats subjected to reperfused reversible (n = 16) and irreversible (n = 16) myocardial injuries. All animals received gadopentetate dimeglumine 1 hour after reperfusion and underwent imaging. Sixteen rats received mesoporphyrin at 2 hours, the other 16 rats received gadopentetate dimeglumine at 24 hours, and all animals underwent imaging at 24 hours.

RESULTS: Mesoporphyrin produced prolonged (22 hours) reduction in T1 in irreversibly, but not in reversibly, injured myocardium. The size of the mesoporphyrin-enhanced region (37% ± 4 [SEM] of left ventricular surface area) closely correlated with the true infarction size as measured by means of histomorphometry (36% ± 3, r = 0.90). The size of the gadolinium-enhanced region overestimated (48% ± 2 and 43% ± 1 at 1 and 24 hours of reperfusion, respectively) the size of true infarction (36% ± 3, P < .05, r = 0.02), but it was close to the size of the area at risk (r = 0.93).

CONCLUSION: The sizes of hyperenhanced regions displayed by using mesoporphyrin and gadopentetate dimeglumine differed from each other. The difference in size of the hyperenhanced region demarcated by mesoporphyrin and gadopentetate dimeglumine may provide an estimation of potentially salvageable myocardium.

Index terms: Gadolinium • Heart, MR, 51.121411, 51.121413, 51.121416, 51.12143, 51.12144 • Magnetic resonance (MR), contrast agents, 511.12143 • Magnetic resonance (MR), echo planar, 511.121416 • Magnetic resonance (MR), inversion recovery, 511.121413 • Magnetic resonance (MR), perfusion study, 511.12144 • Myocardium, infarction, 511.771 • Myocardium, MR, 511.121411, 511.121413, 511.121416, 511.12143, 511.12144


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Reestablishing blood flow to ischemic myocardium after acute coronary arterial occlusion remains the most effective way to limit myocardial infarction and improve ventricular function (1,2). Findings of several clinical and experimental studies (3–9) have indicated that extracellular magnetic resonance (MR) contrast media, represented by gadopentetate dimeglumine, in conjunction with MR imaging may play a role in the visualization of acute infarction and documentation of reperfusion. In normal myocardium, extracellular MR contrast media distribute in a nonspecific manner into the extracellular space. Disruption of the cellular membrane of reperfused myocardium provides an expanded distribution volume for these agents (6,7,10–13). Because of the expanded distribution volume for gadopentetate dimeglumine, this agent causes hyperenhancement of reperfused infarcted myocardium compared with normal myocardium. The hyperenhanced regions demarcated by these media lead to overestimation of the size of acute infarction by 10%–20% (6–9). The cause of overestimation of the infarction on contrast medium–enhanced MR images is most likely inclusion of the periinfarction zone within the hyperenhanced region.

A necrosis-specific MR contrast medium, bis-gadolinium-mesoporphyrin ([hereafter, mesoporphyrin] Gadophrin-2; Schering, Berlin, Germany), recently has become available. Several studies (14,15) in tumors have shown that mesoporphyrin accumulates in necrotic tumor and thrombus. In occlusive and reperfused myocardial infarctions, mesoporphyrin has shown promising results for delineating and sizing necrotic myocardium (15–17). Unlike the standard extracellular gadopentetate dimeglumine (18), binding of mesoporphyrin to necrotic tissue enables prolonged enhancement (14–17).

The specific purpose of this study was to determine whether the regions demarcated by mesoporphyrin and gadopentetate dimeglumine correspond to the area at risk or infarction in rats subjected to 1 hour of coronary arterial occlusion followed by 24 hours of reperfusion. The areas of differential signal intensity on MR images were compared with the sizes of areas at risk and infarction measured by means of histomorphometry. Inversion-recovery echo-planar imaging was used to dynamically measure changes in relaxation time (T1) in myocardium after injection of gadopentetate dimeglumine and mesoporphyrin. Regional T1 measurements were obtained in reperfused reversible and irreversible injury models after 1 hour and 24 hours of reperfusion to confirm that mesoporphyrin is a necrosis-specific agent.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
MR Contrast Media
Both gadopentetate dimeglumine (Magnevist) and mesoporphyrin were prepared and supplied by Schering. The T1 and T2 relaxivities of mesoporphyrin are higher (8.9 and 12 L · mmol-1 · sec-1) than those of gadopentetate dimeglumine (3.7 and 5.6 L · mmol-1 · sec-1). The molecular weights of mesoporphyrin and gadopentetate dimeglumine are 1,697 and 938, respectively. Unlike the standard extracellular gadopentetate dimeglumine, 50%-70% of mesoporphyrin binds to plasma proteins (19,20). Both contrast media are eliminated from the body via the kidneys. The recommended dose of mesoporphyrin is 0.025–0.050 mmol per kilogram of body weight, and median lethal dose in mice is greater than 3.0 mmol/kg; thus, the safety margin is greater than 50–100-fold. This new contrast medium provides prolonged contrast between normal and pathologic tissue that may last for more than 24 hours (16). Gadopentetate dimeglumine is a clinically approved nonspecific extracellular MR contrast medium. It provides relatively short duration of contrast enhancement between normal and pathologic tissue (18). The doses of mesoporphyrin (100 mmol/L solution) and gadopentetate dimeglumine (300 mmol/L solution) were 0.05 mmol/kg and 0.30 mmol/kg, respectively.

Experimental Protocol
All experimental protocols received previous approval from the Committee on Animal Research at our institution and were performed according to the National Institutes of Health guidelines for care and use of laboratory animals. Female Sprague Dawley rats (Simonson Laboratories, Modesto, Calif) were anesthetized with a mixture of 50 mg/kg ketamine hydrochloride (Ketaset; Fort Dodge Labs, Fort Dodge, Iowa) and 1.4 mg/kg xylazine hydrochloride (Anased Injection; Lloyd Labs, Shenandoah, Iowa) administered intraperitoneally. During ventilation, a left thoracotomy at the fourth intercostal space was performed. The anterior branch of the left coronary artery was occluded by placing a size 6.0 snare loop around the artery and a small portion of surrounding muscle. Reperfusion was initiated after 15 minutes to produce reperfused reversible myocardial injury (n = 16) or after 60 minutes to produce reperfused irreversible myocardial injury (n = 16) by releasing the snare occluder from around the coronary artery. No myocardial infarction was expected during the 15-minute coronary arterial occlusion, while infarction was anticipated after 60 minutes of occlusion (21–23). After reperfusion, the snare was left loose inside the chest cavity to allow reocclusion of the artery prior to sacrifice. The coronary reocclusion (after 24 hours of reperfusion) was necessary to define the area at risk with use of intravenous injection of phthalocyanine blue dye via the tail vein. Forty rats were prepared; eight died prior to imaging.

The current study was designed to simulate in a closed chest rat model two possible outcomes of reperfusion therapy: (a) successful reperfusion and absence of myocardial necrosis (ie, reversible myocardial injury) and (b) successful reperfusion and presence of myocardial necrosis (ie, irreversible myocardial injury). The two possible outcomes of reperfusion were defined on the basis of the anticipated effect of coronary arterial occlusion in rats (21–23). Four groups of eight rats per group were used in the current study (Table).


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  		Coronary Arterial Occlusion and Reperfusion in Rats and Regimens of Contrast Media Injection
 
To test the prolonged and necrosis-specific effects of mesoporphyrin, this agent was administered at 2 hours of reperfusion in two groups (groups 1 and 3) of rats subjected to reversible and irreversible injuries, and these animals underwent imaging at 24 hours of reperfusion (Table). The rationale for administering gadopentetate dimeglumine at 1 and 24 hours of reperfusion was that gadopentetate dimeglumine rapidly cleared from the blood and from normal and reperfused infarcted myocardium (18).

Prior to imaging, a catheter was placed in the tail vein for administration of the contrast media. Inversion-recovery echo-planar MR images were acquired before and for 29 minutes after administration of 0.30 mmol/kg gadopentetate dimeglumine by using single-section (at central level of left ventricle) followed by multisection (apex, central, and base of left ventricle) T1-weighted spin-echo imaging. After the first session of inversion-recovery echo-planar imaging and spin-echo imaging, animals in groups 1 and 3 received 0.05 mmol/kg mesoporphyrin at 2 hours of reperfusion. Animals in groups 2 and 4 did not receive mesoporphyrin and underwent imaging after 24 hours of reperfusion. On day 2, the animals in groups 2 and 4 underwent inversion-recovery echo-planar imaging, and T1 was measured before and for 29 minutes after the administration of the second dose of 0.30 mmol/kg gadopentetate dimeglumine. This was followed by T1-weighted spin-echo imaging used to measure the size of the hyperenhanced area. The water content, or wet-to-dry weight ratio, of reperfused reversible, irreversible, and normal myocardium was measured (M.S., J.B., and R.W. together by consensus) (21).

MR Imaging Techniques
Each animal was connected to an electrocardiographic monitor to determine heart rate and to provide a trigger signal for MR imaging. All images were acquired at the end of diastole-early systole phase (QRS wave). A gadolinium-doped phantom (T1 = 0.38 second) was positioned adjacent to each animal to enable standardization of signal intensity. Animals were placed supine in a 5.0-cm-diameter birdcage imaging coil that was then tuned to a proton frequency of 85.6 MHz. The imaging coil was transmit-receive. All MR images were acquired by using a 2-T magnet (Bruker, Fremont, Calif). The bore size and the gradient strength of the scanner were 15 cm and 20 G/cm, respectively.

Inversion-recovery echo-planar imaging.—The single center section of the left ventricle in the axial plane was used to dynamically measure the changes in T1 of normal and injured myocardium before and for 30 minutes after the administration of gadopentetate dimeglumine and at a single time point after the administration of mesoporphyrin at 24 hours of reperfusion. T1 was measured from a set of 20 inversion-recovery echo-planar images in which the inversion time (TI) was incremented to detect the TI with null signal (TInull) for each region of interest (12) (J.B., R.W., and M.S. or M.F.W. together by consensus). The acquisition time of each image was 33 msec, and repetition time was greater than 6 seconds. T1 values were computed from inversion-recovery null point (TInull = T1 x ln2), whereby the apparent T1 value contains no error from T2 or T2* effects. Each set of images was acquired within 2 minutes. It was assumed that the change in relaxation time caused by gadopentetate dimeglumine is proportional to the quantity of gadolinium present within each pixel (12,24).

Spin-echo MR imaging.—T1-weighted spin-echo images were acquired in the axial plane. Multisection spin-echo images of the apex, center, and base of the left ventricle were acquired to (a) measure the magnitude of signal intensity in each section and (b) determine the size of the hyperenhanced region after the administration of the contrast media (15,16). Acquisition parameters for T1-weighted spin-echo images were 300/12 (repetition time msec/echo time msec), a 256 x 128 matrix, a field of view of 50 mm, a 2-mm section thickness, and an acquisition time of 2.5 minutes (7,8,15). The acquisition time of each image was approximately 2.3 minutes, depending on the heart rate. Previous studies in rats (25,26) showed high correlation between infarction size measured from contiguous sections encompassing the entire heart compared with measurements obtained from only two midventricular sections. Therefore, in the current study, three sections (apex, center, and base) were acquired, and all results derived from these three sections are given as mean values. Signal intensities were measured in normal and injured myocardium from the three sections and the phantom (M.S., J.B., R.W.). The change in signal intensity (normalized to phantom) was plotted versus time. In the 1st and 2nd day, the size of the hyperenhanced region on gadolinium-enhanced MR images was measured at 35 minutes after gadopentetate dimeglumine administration and at 22 hours after mesoporphyrin administration (M.S., J.B., R.W. together by consensus). The number of differentially enhanced pixels on the sections were divided by the number of all left ventricular pixels of the three sections to obtain the percentage of the total left ventricular surface area.

Morphometric Measurements
Area at risk.—The area at risk was estimated as previously described (27). In brief, after MR imaging at 24 hours, the coronary artery was reoccluded and 0.20 mL of phthalocyanine blue dye at 37°C was injected into the tail vein. The heart was excised 4 minutes after injection. The atria and right ventricle were removed, and three 2-mm-thick middle slices of left ventricle were prepared corresponding to the location on the MR images. This dye imparts a blue color to perfused myocardium, while the territory of occluded artery (area at risk) remained unstained. The upper and lower surfaces of each slice were scanned with a flatbed scanner connected to a computer (Quadra 650; Apple Computer, Cupertino, Calif), and the region of interest was quantified (by M.S., J.B., R.W.) by using image analysis software (NIH Image, developed at the National Institutes of Health and available on the Internet at http://rsb.inf.nih.gov/nih-image/).

Infarction size.—The reference standard stain for infarction delineation is triphenyltetrazolium chloride (TTC) stain (25,26). Slices from the apex, center, and base, corresponding to MR imaging sections, were incubated in 2% TTC saline solution for 8 minutes at 37°C. Both faces of each slice were then rescanned with the flatbed scanner connected to a computer (MacIntosh; Apple Computer), and the infarction size was quantified by using the public domain NIH Image program. The fractions of both area at risk to total myocardial area of the slice and infarction size to total myocardial area of the slice were measured (by M.S., J.B., R.W.) by means of planimetry from the two sets of images. Histomorphometric measurements were compared with the hyperenhanced region demarcated by MR contrast media (7–9).

Statistics
Descriptive statistics were the mean plus or minus SEM. The signal intensity or T1 and time relations were constructed by plotting the signal intensity or T1 before and after the administration of the contrast medium during the observation period (7,12,21). The paired Student t test was used to determine the difference in T1 and signal intensity before and after administration of contrast medium. The significance of mean differences was determined by using repeat-measures analysis of variance, or ANOVA. This was followed by the Scheffe method with the F test to determine the difference between baseline values and the effect of the contrast medium at each time point during the observation period. The combination of previous methods allowed evaluation of a new MR contrast medium such as mesoporphyrin versus the reference standard extracellular gadopentetate dimeglumine.

Standard linear regression and Bland-Altman analysis were used to determine the agreement between the hyperenhanced region measured on contrast-enhanced MR images and with gross histomorphometry (M.S., J.B., M.F.W., R.W.) (28). According to the Bland-Altman method, the limits of agreement are given as the mean plus or minus SD, where the mean value is the average of the differences between data and is ideally zero but may be either a positive or a negative value plus or minus SD. Provided the differences are normally distributed, 95% of the differences will lie between these limits. The null hypothesis was rejected when the P value was less than .05.


   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
Morphometric Measurements
There was no significant difference in the size of the area at risk between rats that received mesoporphyrin (groups 1 and 3; 50% ± 1 of left ventricular surface area measured in three slices; n = 16) and rats that received gadopentetate dimeglumine (groups 2 and 4; 53% ± 1 of left ventricular surface area; n = 16) or between animals subjected to 15- and 60-minute coronary arterial occlusion. TTC staining exhibited large infarctions in animals (n = 16) subjected to 60-minute coronary occlusion. The location, extent, and size of the infarcted region on mesoporphyrin-enhanced MR images were similar to those determined by means of histomorphometry (TTC stain). There was a linear relationship (r = 0.90) between the size of the enhanced region measured on mesoporphyrin-enhanced MR images (37% ± 4; range, 22%–57% of left ventricular surface area; measured in three slices) and the true infarction size defined by means of histomorphometry (36% ± 3; range, 22%–47% of left ventricular surface area; measured in the same three slices) (Fig 1). The limits of agreement with use of the method described by Bland-Altman were 0.8% ± 9.0 (mean ± 2 SDs) for mesoporphyrin-enhanced MR imaging and TTC-stained mean surface area and 6.2% ± 9.0 for gadolinium-enhanced MR imaging and TTC-stained mean surface area. The difference in the infarction size between mesoporphyrin-enhanced MR imaging and TTC staining showed close agreement, and Bland-Altman analysis disclosed no significant degree of systematic measurement bias (Fig 2).



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  		Figure 1. Bar graph shows comparison between the size of the hyperenhanced region on MR images and the true size of the infarction defined by the reference standard TTC stain (groups 3 and 4). The size of the hyperenhanced region on gadolinium-enhanced (GdDTPA) images did not differ between groups 3 and 4 on day 1. The size of the hyperenhanced region defined on gadolinium-enhanced images significantly decreased on day 2. On both days, the size of the hyperenhanced region defined on gadolinium-enhanced images was significantly larger than the true infarction size defined by TTC stain. The size of hyperenhanced region defined on mesoporphyrin-enhanced images was comparable to the infarction size defined by TTC stain. {dagger} = a P value less than .05 and * = a P value less than .05 for the sizes of the hyperenhanced regions defined on gadolinium-enhanced images compared with TTC-stained infarction sizes, on days 1 and 2, respectively.

 


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  		Figure 2a. Bland-Altman plots show that the limits of agreement were 0.8% ± 9.0 (mean ± 2 SDs) for (a) mesoporphyrin-enhanced MR imaging and TTC-stained mean surface area and 6.2% ± 9.0 for (b) gadolinium-enhanced MR imaging and TTC-stained mean surface area. The difference in the infarction size between mesoporphyrin-enhanced MR imaging and TTC staining showed close agreement, and Bland-Altman analysis disclosed no significant degree of systematic measurement bias.

 


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  		Figure 2b. Bland-Altman plots show that the limits of agreement were 0.8% ± 9.0 (mean ± 2 SDs) for (a) mesoporphyrin-enhanced MR imaging and TTC-stained mean surface area and 6.2% ± 9.0 for (b) gadolinium-enhanced MR imaging and TTC-stained mean surface area. The difference in the infarction size between mesoporphyrin-enhanced MR imaging and TTC staining showed close agreement, and Bland-Altman analysis disclosed no significant degree of systematic measurement bias.

 
The size of the hyperenhanced region on gadolinium-enhanced images (group 3) was 48% ± 2 (range, 37%–61% left ventricular surface area; measured in three slices) at 1 hour of reperfusion, which was significantly larger than the true infarction size of 36% ± 3 (range, 22%–47% of left ventricular surface area; measured in the same three slices; P < .05, paired Student t test) measured in the same animals at 24 hours of reperfusion by using histomorphometry (Fig 1). However, the hyperenhanced region on gadolinium-enhanced images measured at 1 hour after reperfusion was not significantly different from the area at risk determined at 24 hours by means of phthalocyanine blue dye injection (48% ± 2; range, 37%–61% of left ventricular surface area vs 50% ± 3; range, 43%–61% left ventricular surface area; measured in three slices, respectively; r = 0.95).

In animals that received gadopentetate dimeglumine twice (group 4), the size of the hyperenhanced region was 48% ± 2 of the left ventricular surface area (range, 36%–54%; measured in three slices) at 1 hour. The size of the hyperenhanced region was significantly less (43% ± 1; range, 35%–49% of left ventricular surface area; P < .05) after 24 hours of reperfusion. It should be noted that the size of the hyperenhanced region defined at 1 and 24 hours of reperfusion was significantly larger than the true infarction size of 37% ± 2 (range, 27%–42% of left ventricular surface area) at histomorphometry (Fig 1). The Bland-Altman analysis showed no agreement in the mean difference in the infarction size between the two measurements (Fig 2). Regression analysis showed no correlation between the hyperenhanced region estimated at gadopentetate dimeglumine and the true infarcted region at histomorphometry (r = 0.02; slope = 0.02, intercept = 43.5). In contrast, the size of the hyperenhanced region on MR images was not significantly different from the size of the area at risk defined by the phthalocyanine blue dye (48% ± 2 of left ventricular surface area; range, 36%–54% of left ventricular surface area vs 50% ± 2; range, 40%–56% of left ventricular surface area; r = 0.93).

The water content in the normal and the reversibly injured myocardium, or wet-to-dry weight ratio, was not significantly different (4.3 ± 0.1 vs 4.4 ± 0.1; P < .05). TTC staining produced homogeneous brick-red color in the entire surface of the left ventricle in every slice from animals subjected to 15-minute coronary occlusion (n = 16). Reperfused irreversibly injured myocardium (5.1 ± 0.2; P < .05) contained significantly more water than normal myocardium (4.4 ± 0.2) or reversibly injured myocardium (4.3 ± 0.1) at 24 hours of reperfusion. TTC staining produced a homogeneous brick-red color in the normal myocardium (septum and posterior wall) and a pale unstained (infarction) anterolateral wall of the left ventricle in every slice.

Myocardial Enhancement
Reperfused reversible myocardial injury: mesoporphyrin study.—Figure 3 shows a representative set of T1-weighted spin-echo MR images acquired at the apex, center, and base of the left ventricle in a rat subjected to reperfused reversible injury (group 1). At 1 hour of reperfusion, the mean baseline signal intensities of normal and reperfused reversibly injured myocardium were indistinguishable (0.32 arbitrary units ± 0.02 vs 0.34 arbitrary units ± 0.03; n = 8). The magnitudes of enhancement of normal and reversibly injured myocardium were identical after the administration of gadopentetate dimeglumine (0.45 ± 0.04 vs 0.47 ± 0.05; P < .05). Mesoporphyrin caused no increase in the signal intensity of normal (0.36 arbitrary units ± 0.03) or reversibly injured (0.37 arbitrary units ± 0.03) myocardium compared with baseline values; thus, the two regions were indistinguishable (Fig 4).



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  		Figure 3. Multisection sets of axial T1-weighted spin-echo MR images (300/12, matrix of 256 x 128 data points, acquisition time of 2.5 minutes) obtained in a heart subjected to reperfused reversible myocardial injury. The images were obtained (top row) before the administration of contrast medium, (middle row) after the administration of gadopentetate dimeglumine 1 hour after reperfusion, and (bottom row) 22 hours after the administration of mesoporphyrin. MR images were acquired at the same three left ventricular levels to cover the entire heart (25,26). Gadopentetate dimeglumine and mesoporphyrin were unable to delineate reperfused reversibly injured myocardium (anterolateral wall of left ventricle) from normal myocardium (septum), which suggests absence of interstitial edema or necrosis.

 


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  		Figure 4. Line graphs show the effect on regional signal intensity (SI) of gadopentetate dimeglumine administered on (top) day 1 and (bottom) day 2. Precontrast signal intensity provided no evidence of injury. On both days, reperfused irreversibly injured myocardium, unlike reperfused reversibly injured myocardium, showed a differential increase in signal intensity following administration of gadopentetate dimeglumine. This differential increase in signal intensity is most likely attributed to the increase in the distribution volume of gadopentetate dimeglumine in the infarcted region and loss of cellular integrity. * = a P value of less than .05 for reperfused irreversibly injured versus normal myocardium. a.u. = arbitrary units, postisch. = postischemic.

 
On nonenhanced and gadolinium-enhanced inversion-recovery echo-planar images, normal and reperfused reversibly injured myocardium simultaneously passed through TInull, which indicates identical T1 values (Fig 5). Thus, there was no evidence of ischemic injury (Fig 6). At 24 hours of reperfusion (22 hours after mesoporphyrin administration), the T1 values of both the normal and the reperfused regions were comparable to baseline values and identical to each other (Fig 5).



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  		Figure 5. Line graph shows the time course changes in seconds of T1 of normal myocardium and reperfused reversibly injured myocardium following administration of gadopentetate dimeglumine and mesoporphyrin. The pattern of T1 changes after administration of gadopentetate dimeglumine was identical in normal myocardium and reperfused reversibly injured myocardium, which suggests the absence of interstitial edema and infarction. Similarly, mesoporphyrin caused no differential T1 change between normal myocardium and reversibly injured myocardium, which suggests that there is no specific binding between mesoporphyrin and the reversibly injured region.

 


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  		Figure 6. Selected axial inversion-recovery echo-planar MR images (7,000/10, matrix of 64 x 64 data points, acquisition time of 32.7 msec) obtained in a rat (the same animal as in Fig 3) subjected to reperfused reversible myocardial injury. The images were obtained (top row) before the administration of contrast medium, (middle row) after the administration of gadopentetate dimeglumine 1 hour after reperfusion, and (bottom row) after the administration of mesoporphyrin 24 hours after reperfusion. These magnitude intensity images (negative intensity) were obtained with different TI settings. Regions with shorter T1 pass through null intensity at a shorter TI setting. On gadolinium-enhanced images, the left ventricular chamber blood at a TI of 220 msec passes through the null point first, because it has the highest gadopentetate dimeglumine content, followed by normal myocardium and reperfused reversibly injured myocardium at a TI of 420 msec. On precontrast or mesoporphyrin-enhanced images, normal (septum) and reperfused reversibly injured myocardium (anterolateral wall of left ventricle) simultaneously passed through the null point at a TI of 610 msec followed by left ventricular chamber blood at a TI of 820 msec.

 
Reperfused reversible myocardial injury: gadopentetate dimeglumine study.—The signal intensity of reperfused reversibly injured myocardium was indistinguishable from that of normal myocardium on gadolinium-enhanced T1-weighted spin-echo images at 1 and 24 hours of reperfusion (group 2) (Fig 4). These findings were identical to those obtained in group 1 animals after the first dose of gadopentetate dimeglumine was administered. The contrast ratio, or signal intensity of injured to normal myocardium, after gadopentetate dimeglumine administration was not significantly different at 1 hour (1.1 ± 0.3) and 24 hours (1.2 ± 0.3).

Inversion-recovery echo-planar images acquired at 1 and 24 hours of reperfusion showed that both normal and reperfused reversibly injured myocardium passed the null point of longitudinal magnetization at the same TI, which indicates identical T1 relaxation times before the administration of gadopentetate dimeglumine at 24 hours. Gadopentetate dimeglumine caused uniform and equal T1 reduction in both regions during the course of 30 minutes. The washout of gadopentetate dimeglumine, as reflected by serial changes in T1, occurred simultaneously in normal and reperfused reversibly injured myocardium. These findings were identical to those obtained in group 1 animals after the first dose of gadopentetate dimeglumine was administered (Figs 5, 6).

Reperfused irreversible myocardial injury: mesoporphyrin study.—On nonenhanced T1-weighted spin-echo MR images acquired at 1 hour of reperfusion (group 3), there was no significant difference in signal intensity between normal (0.26 arbitrary units ± 0.01) and irreversibly injured (0.25 arbitrary units ± 0.2) myocardium (Fig 4). Gadopentetate dimeglumine caused greater enhancement of the reperfused irreversibly injured myocardium (0.71 ± 0.05; P < .05) than of the normal myocardium (0.43 ± 0.03). The site of injury appeared as a bright zone (Fig 7).



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  		Figure 7. Multisection sets of axial T1-weighted spin-echo MR images (300/12, matrix of 256 x 128 data points, acquisition time of 2.5 minutes) obtained at three left ventricular levels (apex, center, and base) in a heart subjected to reperfused irreversible myocardial injury. The images were obtained (top row) before the administration of contrast medium, (middle row) after the administration of gadopentetate dimeglumine 1 hour after reperfusion, and (bottom row) after the administration of mesoporphyrin 24 hours after reperfusion. Precontrast images show no sign of injury in the anterolateral wall of the left ventricle. On postcontrast images, both MR contrast media are able to delineate reperfused irreversibly injured myocardium as a hyperenhanced zone (arrows) compared with normal myocardium. Note the smaller size of the hyperenhanced area after the administration of mesoporphyrin compared with that after the administration of gadopentetate dimeglumine. Furthermore, mesoporphyrin caused differential enhancement 22 hours after injection, which suggests that there is specific binding between mesoporphyrin and necrotic myocardium.

 
At 24 hours of reperfusion (22 hours after mesoporphyrin administration), the reperfused irreversibly injured myocardium was enhanced substantially compared with normal myocardium (0.39 arbitrary units ± 0.20 vs 0.26 arbitrary units ± 0.02). Mesoporphyrin-enhanced T1-weighted spin-echo MR images demarcated the infarction as a homogeneous, bright region (Fig 7). In contrast, mesoporphyrin produced no increase in signal intensity in normal myocardium.

The series of inversion-recovery echo-planar images acquired after the administration of gadopentetate dimeglumine at 1 hour of reperfusion and at 22 hours after the injection of mesoporphyrin showed considerably greater enhancement of reperfused irreversibly injured myocardium than of left ventricular blood or normal myocardium with both contrast media (Fig 8). Differential reduction in T1 of normal and reperfused irreversibly injured myocardium was observed immediately after the administration of gadopentetate dimeglumine and at 22 hours after the administration of mesoporphyrin. The T1 values were significantly lower (P < .05) for injured compared with normal myocardium after the administration of both contrast media at 24 hours of reperfusion (Fig 9).



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  		Figure 8. Selected axial inversion-recovery echo-planar MR images (7,000/10, matrix of 64 x 64 data points, acquisition time of 32.7 msec) obtained in a heart subjected to reperfused irreversible myocardial injury (from the same animal as in Figs 3 and 7). The images were obtained (top row) before the administration of contrast medium, (middle row) after the administration of gadopentetate dimeglumine 1 hour after reperfusion, and (bottom row) after the administration of 0.05 mmol/kg mesoporphyrin 24 hours after reperfusion. The images in these sets demonstrate that different regions of interest pass the null point of longitudinal magnetization recovery at different TI settings. On gadolinium-enhanced images, reperfused irreversibly injured myocardium (anterolateral wall, arrows) passes through the null point first at a TI of 120 msec, because it has the highest gadopentetate dimeglumine content and the largest distribution volume. This was followed by the left ventricular chamber blood at a TI of 170 msec, which has less gadopentetate dimeglumine content than irreversibly injured myocardium but more than normal myocardium, and finally by normal myocardium. The reperfused irreversibly injured myocardium passed through the null point first at a TI of 270 msec, because it has the highest mesoporphyrin content, followed by the left ventricular chamber blood and normal myocardium at a TI of 570 msec. The difference in T1 effect between the two contrast media is related to the injected dose, distribution volume, and binding of the two agents and the time of imaging after injection.

 


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  		Figure 9. Line graph shows the time course changes in T1 (mean ± SEM) of normal myocardium and reperfused irreversibly injured myocardium following the administration of gadopentetate dimeglumine and mesoporphyrin. The T1 value in seconds of reperfused irreversibly injured myocardium was significantly higher than that in precontrast normal myocardium, which suggests the presence of interstitial edema in the injured region. The reduction in T1 of reperfused irreversibly injured myocardium was significantly greater than that of normal myocardium as calculated by using multiple analysis of variance, which suggests higher gadopentetate dimeglumine and mesoporphyrin contents in necrotic myocardium. Mesoporphyrin data were obtained 22 hours after injection, which suggests that mesoporphyrin specifically binds necrotic myocardium. * = a P value less than .05 for reperfused irreversibly injured myocardium compared with normal myocardium before and after the administration of MR contrast media.

 
Reperfused irreversible myocardial injury: gadopentetate dimeglumine study.—Reperfused irreversibly injured myocardium was indistinguishable from normal myocardium on nonenhanced T1-weighted spin-echo images at 1 and 24 hours of reperfusion (group 4). On gadolinium-enhanced spin-echo images acquired at 1 and 24 hours of reperfusion, the reperfused irreversibly injured myocardium appeared as a homogeneous bright zone (Fig 10). At 24 hours of reperfusion, the signal intensity of normal and irreversibly injured myocardium returned to the baseline level (Fig 4). After the second dose of 0.30 mmol/kg gadopentetate dimeglumine was administered, the contrast (signal intensity of normal myocardium/signal intensity of irreversibly injured myocardium) was slightly but significantly less than that at 1 hour of reperfusion (1.8 ± 0.05 vs 2.0 ± 0.08; P < .5).



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  		Figure 10. Multisection sets of axial T1-weighted spin-echo MR images obtained in an animal subjected to reperfused irreversible myocardial injury. The images were obtained (top row) before the administration of contrast medium, (middle row) after the administration of gadopentetate dimeglumine 1 hour after reperfusion, and (bottom row) after the administration of mesoporphyrin 24 hours after reperfusion. Precontrast MR images showed no sign of infarction. On both days, gadopentetate dimeglumine produced differential contrast between normal myocardium and reperfused irreversibly injured myocardium (arrows), which suggests the presence of interstitial edema and infarction.

 
The series of inversion-recovery echo-planar images acquired after the administration of gadopentetate dimeglumine at 1 and 24 hours of reperfusion showed the difference in the null point of longitudinal magnetization between normal and reperfused injured myocardium. T1 changes in normal and reperfused injured myocardium were identical at day 1 and day 2 (Fig 11). These findings were similar to those obtained in group 3 animals after the first dose of gadopentetate dimeglumine was administered.



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  		Figure 11. Selected axial inversion-recovery echo-planar MR images (7,000/10, matrix of 64 x 64 data points, acquisition time of 32.7 msec) obtained in a heart subjected to reperfused irreversible myocardial injury (from the animal in Fig 10). The images were obtained (top row) before the administration of contrast medium, (middle row) after the administration of gadopentetate dimeglumine 1 hour after reperfusion, and (bottom row) after the administration of mesoporphyrin 24 hours after reperfusion. These images demonstrate that different regions of interest pass the null point of longitudinal magnetization recovery at different TIs. On gadolinium-enhanced images, reperfused irreversibly injured myocardium (anterolateral wall, arrows) passed through the null point first at a TI of 170 msec, because it has the highest gadopentetate dimeglumine content. This was followed by the left ventricular chamber blood at a TI of 270 msec, because it has less gadopentetate dimeglumine content than irreversibly injured myocardium but more than normal myocardium, and then normal myocardium at a TI of 370 msec, because it has the least gadopentetate dimeglumine content.

 
On nonenhanced MR images, the T1 of irreversibly injured myocardium (1,220 msec ± 43) was significantly higher than that of normal myocardium (980 msec ± 30; P < .05). At 24 hours of reperfusion before the administration of the second dose of gadopentetate dimeglumine, the T1 of normal and infarcted myocardium were not significantly different than baseline values, which indicates complete washout of gadopentetate dimeglumine from both regions during the 24-hour interval. Quantitative analysis of regional T1 at 1 and 24 hours of reperfusion indicated that the effect of gadopentetate dimeglumine on the profile of regional T1 was similar to that obtained at 1 hour of reperfusion (Fig 9).


   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
The main findings of the current study were (a) both inversion-recovery echo-planar MR imaging for T1 measurements and T1-weighted spin-echo MR imaging for signal intensity measurements helped confirm that mesoporphyrin is a necrosis-specific agent, (b) mesoporphyrin provided accurate sizing of reperfused infarction compared with findings at histomorphometry, and (c) the region delineated by gadopentetate dimeglumine is closely related to the area at risk—infarcted myocardium and ischemically injured but not infarcted myocardium. Therefore, the difference in size of the hyperenhanced region demarcated by mesoporphyrin and gadopentetate dimeglumine may provide an estimate of salvageable myocardium (Fig 1). A similar difference in size was also measured in rats subjected to 1 hour of coronary occlusion and 1 hour of reperfusion by using phthalocyanine blue dye to measure the area at risk versus technetium 99m–diethylenetriaminepentaacetic acid autoradiography (71% ± 5 of area at risk) or TTC stain (61% ± 3 of area at risk) to measure infarction size (29). To our knowledge, the combined application of gadopentetate dimeglumine and mesoporphyrin as a method to noninvasively estimate the potentially salvageable myocardium at MR imaging has not been previously reported. Accordingly, the use of these two MR contrast media in the same patient might be useful in assessing the effectiveness of therapeutic agents designed to reduce the infarction size.

The optimal MR contrast medium for sizing myocardial infarction should have a long regional residence compared with image acquisition time. The more specific the accumulation of a contrast medium within the necrotic myocardium the better the resultant contrast between viable and necrotic myocardium. The available extracellular MR contrast media are nonspecific agents, and their effects are greatly affected by the presence of interstitial edema and necrosis. Furthermore, they have a short plasma half-life, rapid wash-in and washout, and rapid renal clearance. Findings of several studies (6–9) have shown that the size of the hyperenhanced region is larger than the true infarction size on early images; later it decreases in size owing to washout of the contrast medium from the periphery of the area at risk (30). Therefore, the hyperenhanced region seen on extracellular contrast-enhanced images is affected by the time between the injection of the contrast medium and imaging. On the other hand, Marchal et al (16) found that the size of the enhanced area seen on mesoporphyrin-enhanced images was not affected by the time between the injection of mesoporphyrin and imaging, unlike results with gadolinium-enhanced images.

Chronologic assessment of the gadolinium-enhanced region at 1 and 24 hours of reperfusion indicated that the size of the hyperenhanced region decreased during the elapsed time. A significant diminution (P < .05) in the size of the gadolinium-enhanced region was observed after 24 hours of reperfusion (Fig 1). The reason for this difference in size is not clear from the current study but might be related to the presence of reactive hyperemia occurring in the periphery of the area at risk early after reperfusion or rapid resolution of myocardial edema in the periphery of the injury (periinfarction zone).

Methods for Defining Infarcted Myocardium
Several techniques have been used for the assessment of myocardial injury, although the basis for their use differs. Positron emission tomography demonstrates metabolic activity in dysfunctional myocardium (31), whereas single photon emission computed tomography depicts either intact cell membranes (thallium 201) (32) or mitochondrial function (technetium 99m sestamibi) (33). The contractile reserve of dysfunctional but viable myocardium forms the basis of dobutamine echocardiography (34) and cine MR imaging (35). On the other hand, mesoporphyrin specifically binds to necrotic myocardial cells.

The periinfarction zone has not been evaluated extensively with noninvasive imaging techniques because of the spatial constraints associated with the methods used. Invasive methods have shown that the size of the periinfarction zone varies within (26,36) and between species (eg, 25 mm in dogs [37] and 13 mm in pigs [38]). Contrast-enhanced MR imaging has been used to measure the myocardial area at risk for infarction during occlusion and reperfusion, and the data have been compared with findings at autoradiography and histochemical staining (27,39), but the area at risk and the infarction size were not measured in the same animal. The current study showed that mesoporphyrin provided accurate sizing of the infarction, while gadopentetate dimeglumine could be used to estimate the area at risk in this animal model. These gadopentetate dimeglumine data are in agreement with findings in previous MR studies in rats and dogs (6–9,27,40). We also found that after 1 hour of coronary arterial occlusion and 24 hours of reperfusion 70% of the area at risk became infarcted. These findings are in agreement with the findings of Hale and Kloner (23) in rats in which TTC stain was used and studies in our laboratory in which non-MR methods, such as autoradiography with 99mTc–diethylenetriaminepentaacetic and 201Tl and TTC staining, were used (38,40,41).

Overestimation of reperfused irreversibly injured myocardium on gadolinium-enhanced images can be related to inclusion of an enhanced periinfarction zone. The possible explanations for the increased signal intensity in the periinfarction zone are (a) enlargement of the interstitial space, or edema formation, and increase in the fraction of water that is accessible to the contrast medium; (b) a possibility of leakage of gadopentetate dimeglumine into the intracellular space of some ischemic but viable cells in the periinfarcted region; and (c) vasodilatation and increase in regional blood volume because of the release of several potent vasoactive substances from the necrotic region, such as adenosine, prostaglandin, and histamine, and low pH.

Mechanism of Enhancement
The results of the current study are consistent with the notion that myocardial uptake and retention of mesoporphyrin depends on cellular necrosis (16). The exact binding site of mesoporphyrin in necrotic tissue is not clearly established. Defining the binding site requires measurement of the contrast medium in subcellular compartments, such as the membrane, cytosol, and mitochondria. This was beyond the scope of the current study. In earlier reports (14–18), the authors have speculated that the binding sites of mesoporphyrin are cellular proteins, nucleotides, or calcium precipitates. Physicochemical studies (19,20) have shown that 50%-70% of mesoporphyrin binds to plasma proteins. The greater decrease in T1 of the reperfused irreversibly injured myocardium can be attributed to the presence of a higher concentration of mesoporphyrin. Marchal et al (16) found in rats subjected to prolonged occlusive infarction that the gadolinium content was up to 12-fold higher in infarcted myocardium compared with normal myocardium. For the reasons outlined earlier, mesoporphyrin enabled prolonged enhancement of the reperfused irreversibly injured myocardium but not of reversibly injured myocardium, which suggests that this contrast medium is necrosis specific.

The contrast (signal intensity of injured myocardium/signal intensity of normal myocardium) was greater following administration of gadopentetate dimeglumine (1.69 ± 0.07) than following administration of mesoporphyrin (1.46 ± 0.05; P < .05). This difference in contrast may be attributed to (a) the difference in the dose (0.30 mmol/kg gadopentetate dimeglumine vs 0.05 mmol/kg mesoporphyrin), (b) the difference in the time of imaging after administration (35 minutes after gadopentetate dimeglumine vs 22 hours after mesoporphyrin), and (c) bound versus free contrast medium. However, the difference in contrast cannot be attributed to a difference in heart rate on day 1 and day 2 of imaging because the heart rate was 221 ± 8 beats per minute on day 1 and 224 ± 8 beats per minute on day 2 in this group of animals.

Experiments in rats and dogs have demonstrated that porphyrin compounds, represented by mesoporphyrin and manganese-tetraphenylporphyrin, accumulate selectively in necrotic tissue (18). Because mesoporphyrin provides prolonged enhancement, the need for rapid imaging is not crucial as with nonspecific extracellular MR contrast media. Furthermore, the mesoporphyrin-enhanced spin-echo sequence does not require special hardware or kinetic modeling to define necrotic tissue in reperfused territory. Antimyosin-antibody–labeled magnetopharmaceuticals are another type of infarct-selective MR contrast medium (42). However, the possible immunologic side effects and the complexity in preparation and handling make their clinical feasibility questionable. Another MR contrast medium, gadolinium complex of N3,N6-bis(25-myrisotyloxyethyl)-1,8-dioxo-triethylene-tetramine-N,N,N1-tetraacetic acid (Gd[BME-DTTA]), recently has been developed for the detection of necrotic myocardium (43).

In conclusion, a necrosis-specific MR contrast medium, mesoporphyrin, provides accurate sizing of reperfused infarcted myocardium. The specificity of this agent was confirmed by measuring regional relaxation times and signal intensities in normal and reversibly and irreversibly injured myocardium. The sizes of hyperenhanced regions displayed by using mesoporphyrin and gadopentetate dimeglumine differ from each other. The difference in the size of the hyperenhanced regions produced by the two contrast media may represent the potentially salvageable myocardium. The contrast-enhanced spin-echo approach, described in this study to define necrotic myocardium, is simple and does not require kinetic modeling or special hardware. As shown in this and previous studies (7,10,11,14–17,42,43), contrast-enhanced MR imaging provides a noninvasive method for distinction between regions with different tissue characteristics that depend on cellular integrity. Further studies are needed to assess the fraction of salvageable myocardium in reperfused injury.

Practical applications: At conventional spin-echo T1-weighted MR imaging, the complementary use of bis-gadolinium-mesoporphyrin and gadopentetate dimeglumine maps salvageable myocardium early after reperfusion. The main clinical application of this study is to determine the size of the periinfarction zone from the difference between the regions of enhancement. Differentiation between ischemic but viable myocardium versus necrotic myocardium with use of necrosis-specific MR contrast media may allow a more adequate selection of patients with coronary arterial disease who may benefit from a revascularization procedure. It should be noted that this conclusion is limited by the scope and design of this study. Other practical applications of necrosis-specific MR contrast media in cardiac imaging are (a) distinguishing between ischemic but viable myocardium and nonviable myocardium in reperfused territory; (b) noninvasively monitoring the evolution of myocardial necrosis, or apoptosis, that may develop over time in postischemic myocardium; and (c) evaluating the beneficial effects of therapeutic agents designed to reduce myocardial infarction and preserve the myocardium. Furthermore, necrosis-specific MR contrast media may be useful as markers of cellular necrosis in other noncardiac diseases, such as tumors or inflammatory diseases.


   Footnotes
 
As a member of Schering Berlin, H.J.W. has a financial interest in developing the special paramagnetic contrast medium Gadophrin-2. However, this compound is in an early stage of development and was not commercially available at the time of this writing.

Abbreviations: TI = inversion time TTC = triphenyltetrazolium chloride

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


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 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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