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Measurement of the Distribution Volume of Gadopentetate Dimeglumine at Echo-planar MR Imaging to Quantify Myocardial Infarction: Comparison with ^99mTc-DTPA Autoradiography in Rats¹

¹ From the Department of Radiology, Box 0628, University of California San Francisco Medical Center, 505 Parnassus Ave, Rm L308, San Francisco, CA 94143-0628. From the 1997 RSNA scientific assembly. Received Mar 26, 1998; revision requested May 5; revision received Aug 10; accepted Nov 5. Supported in part by National Institutes of Health grant no. R01 HL52569. H.A. supported by the Swedish Heart Lung Foundation (55501), the Swedish Medical Association (4.0), Hellmuth Herz Foundation, and the Swedish Royal Physiographic Society; J.B. supported by the ADUMED-foundation; and R.W. supported by the Swiss National Science Foundation as research fellows. Address reprint requests to C.B.H.

View larger version (26K): [in a new window]   Figure 1. Schematic drawing of the experimental hypothesis. Extracellular tracers, like gadopentetate dimeglumine and 99mTc-DTPA (the gray areas), distribute rapidly in the extracellular space in normal myocardium, which constitutes about 20% of the myocardial tissue volume—that is, its fractional distribution volume is about 0.2. In reperfused infarcted myocardium, where myocardial cells have lost membrane integrity, the extracellular tracer passively distributes also into the intracellular space of irreversibly injured cells, and the fractional distribution volume approaches 1, or plasma levels. RBC = red blood cell.

View larger version (95K): [in a new window]   Figure 2. Inversion-recovery echo-planar MR images (repetition time, 7,000 msec; echo time, 10 msec) obtained after the administration of 0.1 mmol of gadopentetate dimeglumine per kilogram of body weight of a rat heart subjected to 1 hour of occlusion of the anterior branch of the left main coronary artery followed by 1 hour of reperfusion. The images in this set are chosen to demonstrate that different regions of interest pass the null point of longitudinal magnetization recovery at different inversion time settings. At an inversion time (TI) of 0.1 second, before any substantial recovery has occurred, all tissues have negative signal and are bright. At an inversion time of 0.2 second, the lateral wall of the left ventricle (arrowheads), subjected to ischemia and reperfusion, passes through the null point first (nil signal), because it has the highest gadopentetate dimeglumine content. At an inversion time of 0.3 second, the blood, containing less gadolinium than the reperfused infarcted myocardium but more than the normal myocardium, passes through the null point. At an inversion time of 0.4 second, the normal myocardium, containing less gadolinium than both the blood and the reperfused infarcted myocardium (arrowheads), appears dark as it passes the null point.

View larger version (37K): [in a new window]   Figure 3. Profile of image count density, through a section (X) on an autoradiograph, of a 20-µm-thick midventricular slice from a rat subjected to 1 hour of coronary artery occlusion followed by 1 hour of reperfusion. Three levels of image count density typically were seen: Low count density corresponds to normal (N) myocardium, moderately increased count density (N + 2 SD) in a rim corresponds to putative ischemic injury, and high count density (N x 4) in the core corresponds to infarction.

View larger version (27K): [in a new window]   Figure 4. Plot of R1 and radioactivity ratios of myocardium and blood at various times after the injection of gadopentetate dimeglumine and 99mTc-DTPA after 60 minutes of coronary occlusion followed by 60 minutes of reperfusion. The R1 ratios are from repetitive measurements in the same animals, and the radioactivity ratios are the mean ± SEM from three groups of animals. The R1 and radioactivity ratios for myocardium and blood stayed constant over time, which suggests equilibrium-phase distribution of gadopentetate dimeglumine and 99mTc-DTPA. This means that R1 ratios and radioactivity ratios represent partition coefficients () and allows calculation of fractional distribution volumes. The time-averaged R1 ratios for normal myocardium and blood were slightly higher than the corresponding radioactivity ratios for the three groups (P < .05). For reperfused infarcted myocardium and blood, the R1 and radioactivity ratios were not significantly different.

View larger version (69K): [in a new window]   Figure 5. A, C, Autoradiographs and B, D, flatbed scanned images, from one midventricular slice (20-µm thickness), 15 minutes after the injection of 0.5 mCi (1.85 x 107 Bq) of 99mTc-DTPA in an animal that had been subjected to 1 hour of occlusion of the anterior branch of the left main coronary artery followed by 1 hour of reperfusion. Before the injection of saturated potassium chloride to arrest the heart in diastole, the coronary artery was reoccluded, and phthalocyanine blue was infused to delineate the nonperfused area ("area at risk"). A, The count density is greater in the postischemic region owing to higher 99mTc-DTPA content. Ant = anterior, Inf = inferior, Lat = lateral, Sept = septum. B, Flatbed scanned image shows the perfused area as dark and the area at risk as bright. C, The injured region (region of interest 1) is defined as that with a count density more than 2 SDs greater than the mean value in the normal region (N) (Fig 3). The core of the infarction (region of interest 2) is defined as that having a count density greater than that of the normal myocardium. D, For comparison, region of interest 1 from C has been superimposed on the flatbed scanned image to demonstrate that there is agreement between the injured area (core and rim) and the true area at risk.

View larger version (20K): [in a new window]   Figure 6. Bar graph shows radioactivity ratio (area at risk over normal myocardium) of 99mTc-DTPA from tissue specimens. This ratio is significantly (P < .05) lower than that obtained from autoradiographs (paired data, n = 24). It is likely that specimens, taken from the area at risk, contained both infarcted and noninfarcted myocardium, whereas on the autoradiograph noninfarcted myocardium was excluded.

View larger version (27K): [in a new window]   Figure 7. Graph shows counts per gram per minute for individual specimens of plasma, reperfused infarcted and normal myocardia, and myocardium from control animals versus plasma values of counts per gram per minute calculated from whole blood (hematocrit is 0.45 ± 0.01, n = 24). The values for reperfused infarcted myocardium are obtained by multiplying the ratio of infarcted over normal myocardium in the autoradiograph with counts per gram per minute for normal myocardium. Measured plasma values (n = 17) fall close to the line of identity (not shown), which demonstrates that calculated plasma values are accurate and precise. The values for normal myocardium in the occlusion and reperfusion group and the values for myocardium in the control animals are essentially the same. Counts per gram per minute for reperfused infarcted myocardium are close to plasma values, which suggests that infarcted cells were unable to exclude 99mTc-DTPA. All relations were linear. Plasma: y = 0.94x + 0.03 x 106, r2 = 0.98; reperfused infarct: y = 0.82x + 0.03 x 106, r2 = 0.79; normal: y = 0.13x + 0.01 x 106, r2 = 0.83; control: y = 0.15x + 0.01 x 106, r2 = 0.96. cpm/g = counts per minute per gram, hct = hematocrit.

View larger version (49K): [in a new window]   Figure 8. Infarcted area of high count density (core) on the autoradiograph (left panel), the true infarcted area (bright) defined by using TTC (middle panel), and the true area at risk on the scanned image (right panel) appear to have the same shape, size, and location, which suggests that the core on the autoradiograph represents infarcted myocardium.

View larger version (59K): [in a new window]   Figure 9. Three images, at the midventricular level of the left ventricle, in an animal subjected to 1 hour of occlusion of the anterior branch of the left main coronary artery followed by 1 hour of reperfusion. The reperfused injured zone can be seen as a bright area on all images. A, T1-weighted spin-echo MR image obtained 20 minutes after the administration of 0.1 mmol of gadopentetate dimeglumine per kilogram of body weight with a repetition time of 250 msec and an echo time of 12 msec. B, Inversion-recovery echo-planar MR image obtained 14 minutes after the intravenous injection of 0.1 mmol of gadopentetate dimeglumine per kilogram of body weight (repetition time, 7,000 msec; echo time, 10 msec). The inversion time is set to 220 msec, which produces negative signal in normal myocardium, positive signal in reperfused infarcted myocardium (arrowheads), and nil signal in left ventricular chamber blood. C, Autoradiograph obtained 15 minutes after the intravenous injection of 0.5 mCi (1.85 x 107 Bq) of 99mTc-DTPA.

View larger version (42K): [in a new window]   Figure 10. Bar graph shows fractional distribution volumes of 99mTc-DTPA and gadopentetate dimeglumine in normal and reperfused infarcted myocardia. The fractional distribution volumes are the same in the core of the infarction, whereas they differ slightly in normal myocardium (P < .05). The values in normal myocardium are in agreement with earlier published data (17–24) on myocardial extracellular volume. The values in the core of the reperfused injury are what can be expected from inert passively distributing agents under equilibrium conditions if most myocardial cells have lost cellular membrane integrity.