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Experimental Studies |
1 From the Departments of Radiology (H.A., M.S., C.B.H., D.W.G., J.B., R.W., M.W.D., M.F.W.) and Pathology (P.C.U.), University of California San Francisco, 505 Parnassus Ave, L308, San Francisco, CA 94143-0628. Received February 19, 1999; revision requested April 8; revision received August 25; accepted September 29. Supported in part by NIH grant no. R01 HL52569-01. H.A. supported by the Swedish Heart Lung Foundation, Swedish Medical Association, Hellmuth Herz Foundation, and the Swedish Royal Physiographic Society. J.B. and R.W. supported by the Swiss National Science Foundation. Address correspondence to C.B.H. (e-mail: Charles.Higgins@radiology.ucsf.edu).
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Abstract |
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 TOP Abstract IntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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MATERIALS AND METHODS: Magnetic resonance (MR) imaging and autoradiography were performed in rats subjected to 20, 30, 40, or 60 minutes of regional ischemia followed by 1 hour of reperfusion. The fDVs of gadodiamide injection and 99mTc-DTPA were measured and compared by using inversion-recovery echo-planar imaging and autoradiographic phosphor imaging, respectively.
RESULTS: The mean fDV of both tracers (gadodiamide and 99mTc-DTPA) in normal myocardium was 18% ± 1, whereas that in the entire area at risk increased significantly (P < .05) with 20, 30, 40, and 60 minutes of ischemia to 32% ± 1, 57% ± 4, 66% ± 2, and 68% ± 2, respectively. The fDV was significantly (P < .05) greater in the core of infarction—78% ± 4, 89% ± 5, and 88% ± 5 with 30, 40, and 60 minutes of ischemia, respectively—than in the normal myocardium or in the area at risk.
CONCLUSION: The fDV of MR contrast material in the periinfarcted rim was significantly (P <. 05) greater than that in the normal myocardium, but significantly less than that in the core of infarcted myocardium.
Index terms: Heart, experimental studies, 511.12143, 511.12146, 511.12172 • Heart, MR, 511.121416, 511.12143, 511.12146, 511.12172 • Myocardium, infarction, 511.771 • Myocardium, ischemia, 511.1939 • Myocardium, radionuclide studies, 511.12143, 511.12172 • Radionuclide imaging, experimental studies, 511.12143, 511.12146, 511.12172
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Introduction |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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Investigators (13,14) have found that the distribution volume of iodinated contrast material is inversely related to the distribution of thallium 201 in infarcted myocardium as a marker of viability. The results of other studies (13,15,16) indicate that the concentration of 201Tl in myocardium is related also to the level of perfusion in addition to the integrity of active membrane transport. In a recent study, Pereira et al (17) observed an inverse relationship between 201Tl uptake and the distribution volume of the MR contrast material gadopentetate dimeglumine and a positive relationship between the distribution volume of gadopentetate dimeglumine and the signal intensity change in ex vivo canine hearts.
The feasibility of measuring the myocardial extracellular volume (ie, volume of interstitium plus blood) by using contrast-enhanced MR imaging was described in a study by Diesbourg et al (18), in which a bolus injection followed by constant infusion was used to measure the partition coefficient in normal and ischemic nonreperfused myocardium (occlusive infarction). The constant infusion was used to establish a protracted contrast material steady state in the blood, which allowed time for the contrast material in the ischemic myocardium to equilibrate with that in the blood. This technique was later refined by Tong et al (19) and subsequently used by other investigators (20).
It was previously shown, in rat models of acute reperfused infarction, that ratio values of the change in relaxation rate (
R1) in both normal and infarcted myocardium exhibit a parallel decline with the central blood during gadopentetate dimeglumine clearance (7–9,21); this suggests that the rate of exchange of MR contrast material between myocardium and central blood is much faster than the clearance rate in the kidney. If so, then the fractional distribution volume (fDV) of the agent can be estimated simply from the R1 ratio of myocardium to blood without using constant infusion, and it could be quantified by using MR imaging alone. This rapid equilibration is consistent with the relatively high blood flow in this rat model of reperfused infarction such that the entry of contrast material into the reperfused infarction is delayed by only a few seconds compared with contrast material entry into normal myocardium (5). Saeed et al (5) found that the peak enhancement of left ventricular blood was noted first, followed 2 seconds later by normal myocardial enhancement after the bolus administration of contrast material. The magnitude of signal changes in infarcted myocardium was less pronounced compared with that in the normal myocardium during the peak of the bolus. Enhancement of the infarcted region was delayed, but it increased steadily to a higher value than that in normal myocardium and reached close to plateau enhancement in 2 minutes.
In a recent study (9), it was demonstrated that estimating the fDV of gadopentetate dimeglumine from clearance profiles with MR imaging yields the same values as does estimating the fDV of technetium 99m–diethylenetriaminepentaacetic acid (DTPA) from clearance profiles with autoradiography. The normal myocardium was distinct from the infarcted region at 99mTc-DTPA autoradiography and exhibited an fDV less than that of the infarction.
The current study was the next step in determining the feasibility of quantifying the fDV of MR contrast material in the jeopardized area after an ischemic insult. The aim of this study was to estimate and compare the fDV of gadodiamide injection (Omniscan; Nycomed Amersham, Oslo, Norway) and 99mTc-DTPA in reperfused myocardium in rat hearts subjected to various durations of ischemia in which the reperfused ischemic region was largely viable to completely infarcted.
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MATERIALS AND METHODS |
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Animal Preparation
Sixty-four 240–320-g Sprague-Dawley rats (Harlan, Indianapolis, Ind) were anesthetized with 50 mg/kg sodium pentobarbital and mechanically ventilated after tracheotomy. The methods of coronary arterial occlusion and reperfusion have been described previously (5). Briefly, thoracotomy was performed at the left 4th intercostal space, and a snare ligature was placed around the left anterior descending coronary artery. The artery was occluded for 20, 30, 40, or 60 minutes, after which 1 hour of reperfusion was performed before the administration of the tracers. There were 16 rats in each of the four (20, 30, 40, or 60-minute duration) ischemia groups; in each group, MR imaging was performed in eight rats and radioisotope experiments were performed in eight rats. A catheter was placed in the left jugular vein to deliver gadodiamide or 99mTc-DTPA. Another catheter was placed in a carotid artery to monitor the blood pressure and heart rate and draw blood samples for measurements of 99mTc-DTPA activity in the whole blood and plasma and of the hematocrit level. The arterial pressure (systolic, diastolic, and mean) and heart rate were monitored before the administration of the tracers. Two animals with a mean arterial blood pressure less than 60 mm Hg were euthanized, because autoregulation of myocardial blood flow is lost below this level (22).
Extracellular Tracers
A nonionic gadodiamide injection (Omniscan) and 99mTc-DTPA were used as extracellular tracers. 99mTc-DTPA was prepared in our laboratory before each study. The amount of free-to-bound 99mTc, which was determined immediately after reconstitution by using instant thin-layer chromatography with silicon gel (Gelman Sciences, Ann Arbor, Mich), was less than 1%.
MR Imaging
Half of the animals subjected to occlusion and reperfusion (n = 32) were placed in a supine position into a birdcage resonator that was 5.6 cm in diameter. Copper leads were inserted into a forelimb and the lower part of the abdomen to perform electrocardiographic gating. Electrocardiographically gated images were acquired by using a 2.0-T imaging system (Omega CSI; Bruker Instruments, Fremont, Calif). An inversion-recovery echo-planar imaging sequence was used to measure the T1 values, as previously described (21). After 60 minutes of reperfusion, sets of transverse images were acquired with incremented inversion times. The imaging parameters were as follows: repetition time, greater than or equal to 7 msec; echo time, 10 msec; matrix, 64 x 64 data points acquired in 32.7 msec; section thickness, 2 mm; and field of view, 50 x 50 mm. Regional T1 measurements of the central blood pool and myocardium were obtained in all groups to establish a relationship (ie, R1 ratio) between blood and myocardium. To measure T1, a set of 12–20 inversion-recovery echo-planar images were acquired within a 2-minute interval in which the inversion time varied between 20 and 1,000 msec to define the inversion-recovery null point (TInull) for each region of interest—that is, the left ventricular chamber blood, the noninjured myocardium, and the rim and core of the injured myocardium (Fig 1). T1 values, which were calculated from the relationship T1 = TInull/ln 2, were obtained immediately before and 4, 9, 14, 19, 24, and 29 minutes after the intravenous injection of 0.2 mmol/kg gadodiamide to determine the effect of time on the distribution of the contrast material. The R1 values after the gadodiamide injection were calculated by using the equation 1/T1postcontrast - 1/T1precontrast.
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Autoradiography
The method of quantifying the area at risk and the infarcted area with phosphor imaging (ie, autoradiography) has been described previously (9). Briefly, after occlusion and reperfusion in half the animals (n = 32), approximately 0.5 mCi (18.5 MBq) of 99mTc-DTPA was injected intravenously, and the animals were sacrificed after 5 minutes. Immediately before they were sacrificed, an arterial blood sample (1 mL) was taken to measure the hematocrit level and radioactivity in the whole blood and plasma. The ligature was again closed to produce reocclusion, and 0.25 mL of phthalocyanine blue dye was infused. The heart was excised, the right ventricle was trimmed, and the left ventricle was divided at the midventricular level along the short axis. The apical portion of the heart was used to collect myocardial tissue samples from the area at risk, which was not stained, and from the normally perfused myocardium, which was stained with the phthalocyanine blue dye.
The blood, plasma, and myocardium specimens were weighed, and their radioactivity was measured by using an automatic gamma counter system (Searle Analytic, Tampa, Fla) with the energy window set between 100 and 180 keV. The basal portion of the heart was embedded in a tissue medium (Tissue Tek; Sakura Finetek, Torrance, Calif) for optimal cutting temperature, immediately placed on dry ice, and subsequently cut into several 20-µm-thick slices by using a microtome (Cryocut 1899; Cambridge Instruments, Nussloch, Germany). The slices were placed on a photostimulatable storage phosphor imaging plate (Molecular Dynamics, Sunnyvale, Calif) for 1–2 hours. The phosphor imaging plate was subsequently imaged and digitized (Phosphor Imager: 445 SI; Molecular Dynamics), and the data were evaluated by using a commercially available program (ImageQuant; Molecular Dynamics).
The average count density (counts per pixel) in the regions of interest from the injured and normal myocardium were measured on the autoradiographs. The entire injured region was defined by applying a threshold count density to eliminate pixels with less than the mean value of normal myocardium, as measured in the septum, plus 2 SDs (9). Putative infarction within the area at risk was defined by thresholding out pixels with a mean count density that was less than fourfold greater than that of the normal myocardium. The rationale for defining the infarcted region was that an fDV fourfold greater than that of the normal myocardium would imply that essentially all cells had lost their cellular membrane integrity (9).
To outline the normally perfused area, which was stained blue with phthalocyanine blue dye, and the area at risk, which was not stained, in these animals, the same 20-µm-thick cross-sectional midventricular slices that were used for autoradiography were imaged with a flat-bed imaging unit (Silverscanner IV; LaCie, Hillsboro, Ore) connected to a computer (Quadra 650; Macintosh, Cupertino, Calif). On the resultant digital image, the total cross-sectional left ventricular area at the midventricular level and the unstained area (area at risk) were outlined and measured with computerized planimetry by using a public domain health program that was developed at the U.S. National Institutes of Health and is available on the Internet (23).
Calculation of fDV
It has been reported that the measurement of relative tissue to blood MR contrast material provides an approximation of partition coefficients (19). Assuming that whole blood and myocardial tissue have equal density, the fDV of contrast material in the myocardium (myo) at MR imaging (fDVMRI) and autoradiography (fDVAR) can be calculated as follows:
The fDV of 99mTc-DTPA in reperfused injured myocardium was calculated as the distribution volume in normal myocardium multiplied by the ratio of infarct to normal myocardium on the autoradiographs as follows:
Light and Electron Microscopy
Three hearts were excised and examined by using both light and transmission electron microscopy to demonstrate the presence of membrane integrity loss, measure extracellular space, and count the number of necrotic cells in the ischemically injured territory. The hearts from the two animals subjected to 20 minutes of ischemia and then reperfusion and from one subjected to 60 minutes of ischemia and then reperfusion were arrested in situ with ice cold saline solution and then excised. From the upper midmyocardial slice, one specimen from the nonischemic septum and two from the anterolateral injured wall were excised, and the endocardium and epicardium were trimmed and discarded. The specimens were then quickly minced into less than 1-mm3 sections and immersed into 2.5% glutaraldehyde dissolved in 320 mOsm isotonic phosphate buffer at pH 7.4. The bottom slice immediately adjacent to the slice where the electron microscopic specimens were sampled was used for autoradiography, as described earlier. On the resultant autoradiograph, the areas that corresponded to the areas where the electron microscopic specimens had been taken were evaluated.
For light microscopy, thin slices were cut from several randomly chosen blocks stained with 1% toluidine blue dye and then photographed under x4 and x10 magnification. Toluidine blue was used to distinguish viable cells from nonviable cells on the basis of the uptake of the dye. Nonviable cells uptake the dye, whereas viable cells exclude it. The extracellular space was measured with digital planimetry by using NIH-Image after flat-bed imaging of the light microscopic micrographs. Each image was leveled to make the dark areas (ie, cells stained with 1% toluidine blue) black and the light areas (ie, interstitium and intravascular space) white. White and black pixels were given values of zero and one, respectively. The extracellular space was calculated by dividing the white pixel measurement by the black pixel measurement.
For transmission electron microscopy, thin (70-nm) sections were cut with a microtome (Electron Microscopy Sciences, Fort Washington, Pa) from five to six blocks randomly chosen from the injured area in each animal, and then stained with uranyl acetate and lead citrate before examination. The criteria for reversible injury were intrasarcoplasmic edema, increased lipid droplets, intact sarcolemma, and absence of amorphous matrix densities in the mitochondria, whereas the criterion for irreversible injury (ie, nonviability) was the presence of discontinuous sarcolemma and swollen mitochondria, with amorphous matrix densities signifying irreversible damage (24–26).
Statistical Analyses
Values were expressed as the mean ± SEM, with the number of observations in parentheses. The significance of differences between the mean values was determined by using two-way analysis of variance and deemed to be significant if the P value was less than .05. Subsequent multiple comparisons between groups were performed by using the Tukey t test.
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RESULTS |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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R1) of blood, normal myocardium, and injured myocardium increased significantly after the gadodiamide injection; the maximum R1 occurred at the first data point, 4 minutes after the injection, followed by parallel declines during the 29 minutes of the observation. In the animals subjected to 20 minutes of ischemia, the greatest R1 change was in the chamber blood; this indicated that blood had the highest effective concentration of gadodiamide injection. In contradistinction, in the animals subjected to 30, 40, or 60 minutes of ischemia, the greatest R1 was in the reperfused injured myocardium; this which indicated that the concentration of gadodiamide injection in this region was greater than that in the blood or normal myocardium.
Figure 2 shows the R1 ratios (myocardium/blood) of the rats subjected to 20, 30, 40, and 60 minutes of coronary arterial occlusion followed by 1 hour of reperfusion. The R1 ratios were constant in all groups during the 29 minutes after the gadodiamide injection; this suggested that the rate of exchange of the contrast material between the myocardium (both normal and infarcted) and central blood was much faster than the clearance rate in the kidney. The R1 ratio of hearts subjected to mild (20-minute) regional ischemia was 0.8 ± 0.06, which was significantly (P < .05) higher than the R1 ratio of 0.38 ± 0.05 in the normal myocardium (septum). The postischemic region in these animals showed no evidence of infarction at TTC staining. In the animals subjected to longer (30–60-minute) coronary arterial occlusion, the infarcted region was clearly defined at TTC staining. The size of infarction was the largest in the hearts subjected to 60 minutes of ischemia compared with those subjected to 30 or 40 minutes of ischemia. The R1 ratio of infarcted myocardium was significantly (P < .05) greater than that with mild ischemic injury (Fig 2). In the groups of animals with infarction, the R1 ratio of the infarcted region increased slightly with duration of occlusion.
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The myocardium on the autoradiographs typically showed three different levels of 99mTc-DTPA count density—namely low, moderate, and high (Fig 3). Normal myocardium had relatively low count density. The ischemically injured myocardium had a significantly (P < .05) higher count density. The animals subjected to 20 minutes of occlusion had an injured region with moderate count density. In the cases of occlusion of more than 30 minutes, the injured area consisted of a core of high count density surrounded by a rim of moderate count density; the core increased in size with the duration of occlusion (Fig 3).
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Autoradiography was previously used to measure the sizes of the infarction and area at risk (9). In the animals subjected to 20 minutes of occlusion in the current study, two levels of image count density were seen—namely low count density, which corresponded to normal myocardium, and moderate count density, which corresponded to the area at risk. The autoradiographs showed no high count density, which suggested that there was no evidence of infarction in the animals. The sizes of the area at risk determined by using phthalocyanine blue dye and by using image count density were identical. Autoradiography clearly depicted the difference in infarction size in the animals subjected to 30–60 minutes of occlusion (Fig 5). It should be noted that there was no statistically significant difference in the size of the area at risk between the groups; therefore, the size of the area at risk had no role in the distribution of the tracers.
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Histopathologic Analysis
Three hearts were excised and examined by using light and electron microscopy to demonstrate the consistency in fractional cellular necrosis versus the fDV measured by using MR and autoradiographic imaging. At light microscopy, the normal myocardium showed compact cardiac muscle that consisted of darkly stained, histologically normal myocytes and intact microvasculature (Fig 6). In these three animals, the mean percentage of extracellular space measured by using planimetry was 19% ± 1. The noninfarcted area at risk, which was stained with 1% toluidine blue dye, appeared lightly stained and contained intracellular edema. In two of these animals, the mean extracellular volume measured by using planimetry was 24% ± 2. In one animal, which was subjected to 60 minutes of ischemia followed by 1 hour of reperfusion (Fig 6), the majority of cells were lightly stained and edematous. The space between individual myocytes was small, but the space between myocyte bundles was increased compared with the extracellular volume in the normal myocardium.
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DISCUSSION |
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TOPAbstractIntroductionMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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R1 ratios obtained with contrast-enhanced MR imaging of both normal and injured myocardium exhibited a constant profile, which suggested that the rate of equilibration between myocardium and blood is much faster than the rate of clearance of injected gadodiamide from the central blood. Because the equilibrium state was accomplished, the fDV of the agent could be estimated simply from the R1 ratio of myocardium to blood multiplied by (1 - Hct). (b) The fDVs of all regions (normal myocardium, ischemic but viable periinfarction zone, and infarcted core) were similar for gadodiamide injection and 99mTc-DTPA. Furthermore, the mean fDV of gadodiamide injection in normal myocardium measured by using MR imaging agreed with the extracellular space in normal myocardium measured by using light microscopy (19% ± 1). (c) A characteristic fDV of injured but viable myocardium was identified in the hearts subjected to 20 minutes of occlusion. These animals exhibited moderate injury, with mean fDVs measured by using MR imaging and autoradiography of 0.32 ± 0.01 and 0.28 ± 0.03, respectively. In the current MR imaging study, the proportional R1 ratio of the periinfarction zone was characterized as being approximately twofold greater than that of normal myocardium and approximately half that of infarcted myocardium. The reperfused ischemic region showed no evidence of infarction at autoradiography. (d) On autoradiographs of hearts subjected to longer occlusion (30–60 minutes), an infarcted region and surrounding injured but viable rim (periinfarction zone) were evident. There was little difference in the fDV of the tracer between the periinfarction zone of hearts subjected to 30, 40, and 60 minutes of occlusion and the entire area at risk in the hearts subjected to 20 minutes of ischemia. The fDVs of the infarcted core of hearts subjected to 30, 40, and 60 minutes of ischemia were much greater. The relative size of the moderately increased count density zone diminished as the size of the high count density region expanded.
fDV in Myocardium and Severity of Injury
The fDV and extracellular space values measured by using MR imaging and light microscopy, respectively, were in agreement with earlier published data on extracellular space in normal rat myocardium that were determined histologically or by using tracers (27,28). However, the mean fDV of gadodiamide injection was significantly higher (32% ± 1) in the myocardial regions subjected to 20 minutes of ischemia. This increase may have been due to expansion of the extracellular volume (edema) and the presence of scattered nonviable myocytes. The increase in extracellular volume in mildly ischemic myocardium—that is, that subjected to 20 minutes of occlusion—may have been related to the change in osmotic colloidal pressure due to the leakage of plasma proteins (29) and/or the degradation of the extracellular matrix (30,31).
There is some uncertainty regarding the status of the region defined as a viable rim (periinfarction zone). We assumed that viable rim referred to that region outside of the core of infarction that was ischemic during the occlusion. The identity of the area at risk, as defined by the phthalocyanine blue dye after occlusion versus the elevated count density of 99mTc-DTPA, supported the finding that the rim was ischemic (Fig 5). It was not possible to measure the infarction size by using TTC in the hearts examined with 99mTc-DTPA autoradiography. In a previous study, however, the high count density region equaled the infarction size defined by using TTC (9). Furthermore, in this study, the observed changes in size as a function of occlusion duration were similar to those in previous reports (24,32). Autoradiographs were used to measure the fDV of 99mTc-DTPA in the ischemic but viable area at risk (Fig 4) because they have higher spatial resolution than do inversion-recovery echo-planar images. Because the physical and biologic principles that govern the distribution of 99mTc-DTPA and gadodiamide injection are identical, as shown in Figure 4 and in a previous study (9), the fDVs of 99mTc-DTPA measured are probably valid for gadodiamide injection as well.
The severity of injury in the rim (periinfarction zone), as reflected by the distribution volume of 99mTc-DTPA in the present study, was slightly but not significantly greater than that in the ischemic but viable area at risk after 20 minutes occlusion. This apparent increase in the fDV (Fig 4) of the rim after 20, 30, 40, and 60 minutes of occlusion may have been related to an increasing fraction of scattered necrotic cells; however, it may have been attributable also to contamination from neighboring pixels. Because the rim decreases in size with increasing duration of occlusion, the fraction of the rim pixels immediately adjacent to the core decreases as the core enlarges with duration of occlusion.
The results of a recent study (33) involving high-spatial-resolution gadopentetate dimeglumine–enhanced, T1-weighted spin-echo imaging provided new evidence regarding the presence of the ischemic but viable rim. The study results showed a diminution in the size of the gadopentetate dimeglumine hyperenhanced region after 24 hours compared with the region size after 1 hour of reperfusion in rats subjected to 1 hour of occlusion. The size of the hyperenhanced region after 1 hour of reperfusion was similar to that of the area at risk measured postmortem. The reduction in size of the hyperenhanced myocardium suggested that the rim most likely consisted of viable myocytes. Furthermore, there was a substantial difference in the size of the hyperenhanced region on the necrosis-specific and standard extracellular contrast-enhanced MR images.
The results of previous studies (7,9,21) have shown that the maximum change in myocardial T1 occurs 5 minutes after the administration of the contrast material. In these studies, the R1 ratios of normal and injured myocardium were constant; this suggests that the rate of equilibration between myocardium and blood is much faster than the rate of clearance of injected gadodiamide from the central blood. The constant R1 ratio over the course of 29 minutes, as seen in the current study and in previous studies (7,9,21), suggests that the perfusion in the infarcted region is adequate. During the clearance phase, disequilibrium would cause the clearance of the agent from the tissue to slow its clearance from the blood, and the R1 ratio would increase over time to a delayed plateau. In this situation, the concentration of contrast material in the tissue would exceed that in the blood, and the fDV would be overestimated.
Kinetics of Myocardial Enhancement
The results of previous reports have suggested two mechanisms by which gadolinium chelate contrast material causes differential enhancement: (a) altered wash-in and wash-out kinetics in the injured area compared with those in normal myocardium (34,35) and (b) changes in the distribution volume of the contrast material (6–9,17–21). The results of this study support the notion that the major mechanism by which gadolinium-based contrast material causes enhancement in ischemically injured myocardium is change in fDV of contrast material.
The time of enhancement of the infarcted region depends on several factors, such as whether the injury zone is occluded or reperfused or subacute or chronic, the presence of collateral flow, the durations of ischemia and reperfusion, the size of the infarction and hemorrhagic zone, the presence of a no-reflow zone, the contrast material administration rate (ie, bolus versus slow infusion), and animal species variations. Close to maximum enhancement was achieved 2 minutes after the contrast material injection in the rats subjected to 1 hour of occlusion and 1 hour of reperfusion (5). In this acute rat model of myocardial injury, the size of infarction had no effect on the equilibration of the contrast material. In subacute and chronic infarctions, heterogeneous functional vascularity may have a more important role.
The relevance of the acute infarction model used in the current study for implications to ischemic heart disease in humans has to be considered. In patients with acute myocardial infarction, both homogeneous (32,33) and inhomogeneous enhancement patterns have been observed at contrast-enhanced MR imaging (34–37). The latter pattern often consists of a hypoenhanced central core surrounded by a hyperenhanced rim (26,32,35,38). This type of enhancement pattern is usually discussed in relation to success or failure to establish reflow to the injured area and/or the presence of a no-reflow zone (35,39). Accordingly, a constant R1 ratio may not be achievable with a single contrast material injection in these patients, in which case the constant infusion technique might be necessary. The optimal constant infusion technique described by Tong et al (19) was used to rapidly establish a steady-state concentration of the contrast material in the blood, which allowed time for the extracellular small tracers such as gadopentetate dimeglumine to irrigate the entire infarcted region. The major limitations of contrast-enhanced MR imaging for measuring myocardial viability have been recently discussed (40).
Limitations
In the current study, MR imaging and radioisotope measurements were not performed in the same animals. Because of technical limitations, the sizes of the regions with high density counts in the hearts subjected to different durations of occlusion were not directly correlated with the true infarction size measured by using TTC. However, this type of correlation was performed in a recent study (9,32). The current study was performed in hearts subjected to a brief reperfusion period. Further studies on animals subjected to prolonged reperfusion and in other species of animals are needed before the findings can be extrapolated to patients.
Inversion-recovery echo-planar imaging, as used in this study, did not provide sufficient spatial resolution to discriminate the rim from the core of infarction in the majority of cases. The use of higher resolution imaging techniques, such as T1-weighted, segmented, turbo fast low-angle imaging, as described by Pislaru et al (41), may help to define this region on the basis of the markedly different R1 values for normal, ischemic but viable, and necrotic regions.
In conclusion, measuring the fDV of MR contrast material by using inversion-recovery echo-planar MR imaging can provide information about the status of ischemically injured myocardium. The data suggest that a moderate (~30%) increase in fDV is caused by an expanded extracellular volume and the presence of scattered nonviable myocytes, whereas a high (>80%) fDV indicates complete infarction.
Practical applications: Measurement of the fDV with contrast-enhanced MR imaging facilitated the identification of a potentially salvageable periinfarction rim after severe ischemia. This technique may be useful for evaluating the drugs and interventional procedures used to reduce infarction size.
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Acknowledgments |
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Footnotes |
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R1 = change in relaxation rate
TTC = triphenyltetrazolium chloride Author contributions: Guarantors of integrity of entire study, M.S., C.B.H., M.F.W.; study concepts and design, M.S., C.B.H., M.F.W.; definition of intellectual content, M.S., C.B.H., M.F.W.; literature research, H.A., M.S.; experimental studies, H.A., M.S., D.W.G., P.C.U., J.B., R.W., M.F.W.; data acquisition, H.A., M.S., D.W.G., P.C.U., J.B., R.W., M.F.W.; data analysis, H.A., M.S., D.W.G., M.F.W.; statistical analysis, H.A., M.S.; manuscript preparation, H.A., M.S.; manuscript editing, H.A., M.S., C.B.H., M.F.W.; manuscript review, all authors.
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References |
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 M. Saeed New Concepts in Characterization of Ischemically Injured Myocardium by MRI Experimental Biology and Medicine, May 1, 2001; 226(5): 367 - 376. [Abstract] [Full Text]
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M. Saeed, G. Lund, M. F. Wendland, J. Bremerich, H.-J. Weinmann, and C. B. Higgins Magnetic Resonance Characterization of the Peri-Infarction Zone of Reperfused Myocardial Infarction With Necrosis-Specific and Extracellular Nonspecific Contrast Media Circulation, February 13, 2001; 103(6): 871 - 876. [Abstract] [Full Text] [PDF]
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G. K. Lund, C. B. Higgins, M. F. Wendland, N. Watzinger, H.-J. Weinmann, and M. Saeed Assessment of Nicorandil Therapy in Ischemic Myocardial Injury by Using Contrast-enhanced and Functional MR Imaging Radiology, December 1, 2001; 221(3): 676 - 682. [Abstract] [Full Text] [PDF]
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), 30 (
), 40 (
), and 60 (
) minutes of coronary arterial occlusion followed by 1 hour of reperfusion. Note that the 
