(Circulation. 1995;92:1902-1910.)
© 1995 American Heart Association, Inc.
Articles |
Physiological Basis of Myocardial Contrast Enhancement in Fast Magnetic Resonance Images of 2-Day-Old Reperfused Canine Infarcts
From the Departments of Radiology (R.M.J., C.H.L.-O., P.C., V.M., E.A.Z.) and Medicine (M.A., T.K., J.A.C.L., L.C.B.), Johns Hopkins University, Baltimore, Md.
Correspondence to Robert M. Judd, PhD, Johns Hopkins University, 143 MRI Bldg, 600 N Wolfe St, Baltimore, MD 21287. E-mail judd@mri.jhu.edu.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Contrast-enhanced fast magnetic resonance (MR) images of acute, reperfused human infarcts demonstrate regions of hypoenhancement and hyperenhancement. The relations between the spatial extent and time course of these enhancement patterns to myocardial risk, infarct, and no-reflow regions have not been well characterized.
Methods and Results The proximal left anterior descending coronary artery was occluded in 11 closed-chest dogs for 90 minutes followed by 2 days of reperfusion. Regional blood flow was determined by use of radioactive microspheres. The animals were studied at the 2-day time point with contrast-enhanced fast MRI (Signa 1.5 T, General Electric). Thioflavin-S was administered to demarcate no-reflow regions. The hearts were then excised, sectioned into five base-to-apex slices, stained with 2,3,5-triphenyltetrazolium chloride (TTC), and photographed under room light (for TTC) and ultraviolet light (for thioflavin). The spatial extents of thioflavin-negative, TTC-negative, and risk regions were compared planimetrically with MRI hypoenhanced and hyperenhanced regions. The spatial locations of subendocardial hypoenhancement in MR images correlated closely with those of thioflavin-negative regions. Microsphere blood flow in these regions was significantly reduced compared with remote regions (0.37±0.09 versus 0.88±0.10 mL/min per gram, respectively, P<.001) and with baseline (0.37±0.09 versus 0.87±0.15 mL/min per gram, P<.01). The spatial extent of hyperenhancement was smaller than the risk region (r=.64, slope=0.48, P<.001) but highly correlated with TTC-negative regions and were, on average, 12% larger (r=.93, slope=1.12, P=.035).
Conclusions In contrast-enhanced MR images of 2-day-old reperfused canine infarcts, myocardial regions of hypoenhancement are related to the no-reflow phenomenon. Approximately 90% of the myocardium within hyperenhanced regions is nonviable.
Key Words: perfusion • magnetic resonance imaging • contrast media • myocardial infarction • reperfusion
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Reestablishing perfusion to regions of acute MI is an important determinant of long-term prognosis.1 2 3 The success of attempts to reperfuse via thrombolytics, angioplasty, or bypass surgery typically has been evaluated with angiography,4 but this technique addresses only the issue of large-vessel patency. The question of whether or not reperfusion has been reestablished at the microvascular level has usually been addressed by use of nuclear medicine techniques such as thallium scintigraphy.5 6
Over the past several years, a number of experimental studies have suggested that contrast-enhanced MR imaging could be used to characterize microvascular perfusion.7 8 9 10 11 12 13 14 Early studies using spin-echo imaging required several minutes to obtain each image of the heart.10 11 12 13 14 More recently, several groups have used fast MR imaging to characterize the myocardial first pass of MR contrast agents after bolus administration.8 15 Our group recently reported the use of fast MR to examine myocardial enhancement over a time scale of minutes in acute, reperfused human infarcts.16 These studies have demonstrated that when the infarct-related artery remains occluded, myocardial image intensity in the area perfused by that artery is reduced compared with normal myocardium after contrast administration.14 15 17 Conversely, in those infarcts that are successfully reperfused, myocardial image intensity is increased compared with normal myocardium.10 13 14 16 18
Ultimately, the potential of contrast MR to provide information about microvascular perfusion will be determined by the relation of these altered enhancement patterns to the underlying pathophysiology. Many key issues concerning the relation of flow to hypoenhancement and hyperenhancement in contrast-enhanced MR images of the heart remain poorly understood. In the present study, we examined the relation between regional myocardial blood flow and MR contrast-enhancement patterns in a closed-chest canine model of acute, reperfused MI. This canine model has been well characterized by our group19 and results in well-defined regions of ischemic myocardium at risk, infarcted myocardium, and regions of no-reflow that can be delineated by established methods.19 The imaging methods used in the present study were identical to those of our clinical study16 to facilitate comparison with the images obtained from patients.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Experimental Preparation
Eleven mongrel dogs weighing 20 to 25 kg were studied. The care and treatment of all animals involved in this study were in accordance with institutional guidelines. On day 1, the animals were anesthetized with sodium pentobarbital (35 mg/kg IV), intubated, and mechanically ventilated. A catheter sheath was placed into the right femoral artery and used to introduce a 6F pigtail catheter into the LV under fluoroscopic guidance. This catheter was used for microsphere administration and to monitor LV pressure. The sheath of this catheter was used for microsphere reference sampling from the femoral artery. A second catheter sheath was then placed in the left femoral artery and used to introduce a 7F left Judkins 2.5 guiding catheter into the left main coronary artery. A 3.5F angioplasty balloon catheter was passed through the guiding catheter and slid into the LAD over a 0.014-in guide wire that was positioned in the proximal LAD. The balloon was then inflated for 90 minutes to produce myocardial infarction and then deflated to allow reperfusion of the infarcted myocardium. Regional flow was measured immediately before LAD occlusion, 80 minutes after LAD occlusion, and 3.5 hours after reperfusion (Fig 1
) by LV
injection of 
2 million sonicated microspheres19
(15±1 µm in diameter) labeled with one of several radionuclides
(153Gd, 113Sn, 103Ru,
95Nb, or 46Sc; Du Pont). The animals were then
allowed to recover.
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MR Imaging
All images were acquired after 48 h of reperfusion
(Fig 1
). The
dogs were again anesthetized and mechanically ventilated, and a
pigtail catheter was placed in the LV under fluoroscopic guidance. A
fourth set of microspheres was administered, and the animals
were transported to the MR facility for scanning in a whole-body
1.5-T Signa scanner (General Electric). The animals were placed in the
right antecubital position, and a flexible radiofrequency receiver coil
was placed around the chest. Scout images were obtained to locate the
long axis, from which four (n=6) or six (n=5) parallel
short-axis
slices were prescribed. ECG-gated mid-diastolic fast MR
images were then acquired by use of a pulse sequence that provides a
linear relation between image intensity and contrast concentration over
a wide range and that has been described in detail
elsewhere.20 21 Briefly, magnetization is driven to
steady
state before image acquisition using a train of dummy radiofrequency
pulses, resulting in strongly T1-weighted images with
little or no influence of T2 and/or T2*.
Imaging parameters were image matrix 256x96, 
=45°,
TR=6.5 ms, TE=2.3 ms, field of view 32 cm, and slice
thickness=10 mm.
Voxel dimensions were 1.2x3.3x10 mm.
The time line for MR
imaging is shown in Fig 2. The
effects of cardiac motion were minimized by acquiring only one fourth
of each image (24 phase encodes) in each cardiac cycle. All image data
were acquired during breath hold, which was achieved by turning off the
respirator at end expiration. Typically, breath-hold duration was
32 cardiac cycles, during which each of the four (or six) base-apex
locations were imaged twice (Fig 2).
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After baseline
precontrast images were acquired, 0.1 mmol/kg of a
nonionic clinically approved MR contrast agent (gadoteridol, ProHance,
Squibb) was injected by hand as a bolus into a femoral vein. Images
were then acquired beginning 10 seconds after contrast injection. After
the 32 cardiac cycles required for image acquisition, the animal was
ventilated for 30 seconds, after which the second cycle of image
acquisition began (Fig 2). This cycle was repeated for 15
minutes. If
the 10 seconds to begin imaging and 10 seconds to turn the respirator
on and off are accounted for, the effective temporal resolution between
any two images of the same base-apex location was approximately 30
seconds.
Measurement of Risk, Infarct, and No-Reflow Regions
Immediately after MR imaging, 20 mL of the fluorescent
dye thioflavin-S (2% solution) was injected into the LV via the
pigtail catheter to define the extent of the no-reflow
region.19 One minute after thioflavin injection, the
hearts were arrested with potassium chloride and excised. The atria,
epicardial fat, valvular tissue, and right
ventricular free wall were trimmed away. The LV was then
sectioned into five short-axis slices, each of which was then
incubated in a 2% solution of TTC for 20 minutes at 37°C. Regions
that failed to demonstrate brick-red staining were considered to
represent infarcted myocardium.22 Each
slice was then photographed under ultraviolet light (for thioflavin)
and room light (for TTC). For each slice, shallow cuts were made to
divide 50% of the LV circumference centered in the infarcted region
into 8 to 12 pie-shaped sections. An additional pie-shaped
section was identified on the side of the ventricle opposite the
infarcted region for measurement of blood flow in a remote region. The
exact locations of these cuts were recorded before the slices were
photographed to relate thioflavin and TTC regions to the location from
which tissue samples were taken for microsphere blood flow
analysis.
After the slices were photographed, myocardial samples (0.1
to 0.5 g)
were obtained for microsphere counting. For each slice, each of
the pie-shaped sections was divided into five approximately equal
regions from epicardium to endocardium, yielding a total of 250
myocardial samples from each heart. Each of the samples was then
weighed and counted in a gamma emission well spectrometer (model 5986,
Hewlett-Packard) along with the reference blood samples at appropriate
energy windows. Regional myocardial blood flow (mL/min per 100 g) was
then calculated by standard methods.19
Subsequently, clear acetate sheets were placed over projections of the photographs, and the infarcted regions (TTC negative) and no-reflow regions (absence of thioflavin) were outlined by hand. The risk regions were defined as areas in which myocardial blood flow (based on the microspheres) was reduced by at least 50% during the occlusion compared with remote (nonischemic) regions. With this definition, the location of each of the myocardial tissue samples within the risk region was transferred to the acetate sheets. This process was guided by knowledge of the locations of the cuts recorded before photography and by the fact that the epicardial and endocardial samples were of equal size. The areas of the risk, infarct, and no-reflow regions were then measured by planimetry of the acetate sheets and combined with the weight of the slices to calculate the size of these regions as a percentage of LV mass.
Regional Blood Flow
To compare blood flow within different
myocardial regions,
within each animal the myocardial samples were grouped into four
regions: remote, at risk but not infarcted, infarcted but not
no-reflow, and no-reflow. For each animal, blood flow in the
remote region was defined as the transmural average of blood flow in
normal myocardium. Blood flow in the "at risk but not
infarcted" region was determined by averaging all samples within the
risk region but outside the TTC-negative zones. Blood flow in the
"infarcted but not no-reflow" region was determined by
averaging all samples within the TTC-negative zones but outside the
thioflavin-negative zones. Blood flow in the "no-reflow"
regions was determined by averaging all samples within the
thioflavin-negative zones. Samples that were partially located in
more than one zone were excluded from the blood flow calculations.
Measurement of Hypoenhanced and Hyperenhanced Regions
The
surface areas of hypoenhanced and hyperenhanced regions in
the MR images were measured planimetrically by two independent
observers blinded to the histological results. These
regions were identified for each slice directly from the images on a
Macintosh using the software package NIH IMAGE. For each
slice, the delineation of regions of hypoenhancement was improved by
averaging four images acquired within the first 2 minutes after
contrast arrival in normal myocardium. The delineation of
hyperenhanced regions was facilitated by averaging eight images
acquired 6 to 14 minutes after contrast. The spatial extents of
hypoenhanced and hyperenhanced regions were expressed as percent
LV.
Time-Intensity Curves
Myocardial MR image time-intensity
curves were generated
within regions of interest using NIH IMAGE. Regions of
interest were placed within the hypoenhanced and hyperenhanced regions,
as well as within the LV cavity and within normal
myocardium (remote). Care was taken to define the regions
of interest several pixels from the epicardial and endocardial surfaces
to avoid partial-volume effects. The image time-intensity
curves were normalized by two different methods. With the first
normalization method, image intensities within the four regions (blood,
remote, hypoenhanced, and hyperenhanced) were expressed as the percent
increase in image intensity compared with baseline by use of the
following equation:
 | (1) |
With the second normalization method, the percent change in myocardial image intensity was divided by the percent change in blood image intensity at each time point. We term this second normalization method the MBSI.
 | (2) |
The MBSI was used to test the hypothesis that the kinetics of contrast enhancement in the remote, hypoenhanced, and hyperenhanced regions were the same as those in the blood pool.
Statistical Analysis
Repeated-measures ANOVA23
was used to
test the hypotheses that microsphere blood flow varied with
time in different regions and that image intensities varied with time
in different regions. Differences between specific regions were
isolated with Bonferroni-corrected t tests. The spatial
extents of hypoenhanced and hyperenhanced regions were then compared
with those of thioflavin-negative, risk, and TTC-negative regions
by paired t tests. Differences were considered significant
at the 5% level. Linear regression analyses were used to
compare hypoenhanced regions with thioflavin-negative regions,
hyperenhanced regions with risk regions, and hyperenhanced regions with
TTC-negative regions. All results are expressed as mean±SEM.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Hemodynamics
The Table
summarizes the
hemodynamic results before, during, and after occlusion
of the proximal LAD. The hemodynamic changes were
typical of those observed during myocardial infarction and
reperfusion.
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Microspheric Blood Flow
Fig 3 shows
microspheric blood flow immediately
before occlusion (baseline), 80 minutes after onset of occlusion, and
after 3.5 and 48 hours of reperfusion in the four different myocardial
regions: (1) remote, (2) at risk but not infarcted, (3) infarcted but
not no-reflow, and (4) no-reflow. At baseline, blood flow
averaged across all regions was 0.71 mL/min per gram, and differences
between regions were not statistically significant. During the
occlusion, a highly significant decrease in flow was observed in
regions 2 through 4 compared with baseline (P<.001) and
remote regions (P<.001), as would be expected, with
virtually no flow in region 4 (the region that was thioflavin negative
at 48 hours). After 3.5 hours of reperfusion, blood flow in all regions
increased to values similar to those at baseline (P=NS for
flow at 3.5 hours compared with baseline), demonstrating that the
myocardium had been successfully reperfused. After 48 hours
of reperfusion, blood flow in regions 2 (risk) and 3 (infarcted) was
slightly lower than in remote regions (P=NS) but higher than
in region 4 (no-reflow, P<.05). Blood flow in the
no-reflow region was less than half that in remote regions
(0.37±0.09 versus 0.88±0.10 mL/min per gram, respectively,
P<.001).
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Imaging Results
Fig 4 depicts typical MR
images acquired in one dog
before contrast administration and at various times after contrast. Fig
5A depicts average image time-intensity curves
obtained in all 11 dogs in blood and in three myocardial regions. Fig
5B shows the same myocardial data as Fig 5A on
an expanded scale.
Before contrast administration, image intensity in blood and in all
myocardial regions was homogeneous and low,
consistent with the design of the imaging pulse
sequence20 21 and our observations in
humans.16 21 After contrast administration, three
distinct
myocardial enhancement patterns were apparent. The first pattern,
observed in normal myocardial tissue (remote), involved a
homogeneous increase in myocardial image intensity within 1
minute, followed by a decline in intensity for the remaining 14 minutes
(P<.001). The second pattern, hypoenhancement, was observed
in 8 of the 11 animals and involved the central subendocardial regions
of the infarct zones. These regions of hypoenhancement were most
apparent during the first 2 minutes after contrast administration.
Image intensity within these regions increased slowly throughout the
15-minute imaging period (P<.001). The third pattern,
hyperenhancement, was observed in 10 of the 11 animals. These
hyperenhanced regions appeared similar to normal myocardium
during the first 2 minutes after contrast but then became progressively
better delineated about 5 minutes after contrast and remained so for
the duration of the 15-minute imaging period. Image intensity in these
regions did not change after 2 minutes postcontrast
(P=NS).
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Fig 6 shows the MBSI for the
same data as shown in Fig 5. In normal myocardium, the MBSI
reached a value of 0.2
within the first 2 minutes after contrast and remained constant
thereafter. No statistically significant changes in the MBSI were
observed after 2 minutes (P=NS), suggesting that contrast
kinetics in normal myocardium were essentially the same as
those of the blood pool. In hypoenhanced myocardium, the
MBSI increased slowly throughout the imaging period
(P<.001). In hyperenhanced myocardium, the MBSI
also increased throughout the imaging period (P<.001). The
increases in MBSI over time in hypoenhanced and hyperenhanced regions
strongly suggest that contrast kinetics in these regions, unlike normal
myocardium, are dissociated from those of the blood
pool.
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Relationship of Hypoenhancement to No-Reflow Regions
Fig
7 compares typical MR images obtained in two
different dogs within the first 3 minutes after contrast to the
photographs of thioflavin deposition obtained postmortem.
Qualitatively, a strong similarity was observed between the location of
the hypoenhanced regions in the MR images and the absence of thioflavin
deposition. Similar results were observed in all eight of the dogs in
which hypoenhancement was present. In the remaining three dogs, no
regions of hypoenhancement were detected. In each of these three
animals, the infarct was very small (<2.5% of ventricle based on
TTC), and the photographs of thioflavin deposition revealed very small
(<3 mm) subendocardial no-reflow regions in two animals and none
in the other animal.
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Fig 8 is a plot of the spatial
extent of the
hypoenhanced regions, expressed as a percentage of the total LV mass,
against the extent of the no-reflow. Hypoenhanced regions were
smaller than thioflavin-negative regions (0.98±0.26% versus
2.50±0.79%, P<.05; ranges, 0% to 2.3% and 0% to 7.9%,
respectively). On average, the size of the hypoenhanced regions was
25% of the size of the thioflavin-negative regions
(r=.75, slope=0.25).
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To examine whether the
smaller size of the hypoenhanced regions was due
to the level of blood flow required for detection, we computed the
percent LV with microsphere flows less than 0.1, 0.2, 0.3, and
0.4 mL/min per gram and compared them with the size of the hypoenhanced
and thioflavin-negative regions. The results are shown in Fig
9. The mean size of the hypoenhanced regions was similar
to the mean size of myocardium receiving flow <0.1 mL/min
per gram. Conversely, the mean size of thioflavin-negative
regions was closer to the mean size of myocardium receiving
flow <0.2 mL/min per gram. The results shown in Fig 9
suggest that
hypoenhanced regions are smaller than thioflavin-negative regions
because the MR contrast agent molecule (gadoteridol) can be delivered
in sufficient amounts to be detected at lower flows than the
thioflavin-S molecule. Because gadoteridol and thioflavin-S have
similar molecular weights (600 D for both), this difference may be
due to a requirement for higher concentrations of thioflavin before the
myocardium appears stained in ultraviolet photographs.
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Relationship of Hyperenhancement to Infarct and Risk
Regions
Fig 10 compares typical MR images obtained in
2
different dogs 10 minutes after contrast administration with the
photographs of the TTC-stained myocardium obtained
postmortem. Qualitatively, the location of the hyperenhanced regions
was always concordant with the location of the infarct. Similar results
were observed in 10 of the 11 dogs. The 1 animal in which
hyperenhancement was not observed had a very small infarct (2.6% of
ventricle).
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The sizes of hyperenhanced regions (8.4±2.2%; range, 0% to 24%) and risk regions (23.5±2.9%; range, 2.4% to 38%) were only modestly correlated and were approximately half as large (r=.64, slope=0.48, intercept=-3.0). The differences were statistically significant (P<.001).
The sizes of hyperenhanced regions
were strongly correlated with
TTC-negative regions (6.4±1.8%; range, 0.7% to 20%). Fig
11 is a plot of the sizes of the hyperenhanced regions
compared with the sizes of the TTC-negative regions. A straight line
fit through these data had an r value of .93 and
coefficients of 1.12 (slope) and 1.17 (intercept). However, the
hyperenhanced regions were slightly larger than TTC-negative regions
(12%), and this difference was statistically significant
(P=.035).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study demonstrates that there is a relation between MR contrast-enhancement patterns and the extent and type of myocardial injury. Comparison of contrast-enhanced MR images to histology showed that in hearts subjected to 90 minutes of LAD occlusion followed by 48 hours of reperfusion, hypoenhanced regions are related to the no-reflow phenomenon and that
90% of the myocardium
within hyperenhanced regions is nonviable.
Time-Intensity Curves
The initial slopes of the
time-intensity curves for the
remote, hypoenhanced, and hyperenhanced regions (Fig 5)
appeared to
reflect regional variations in myocardial blood flow as measured by
microspheres (Fig 3). Flow at 48 hours (Fig 3)
was lowest in
the thioflavin-negative regions, which also had the smallest
initial slope in the time-intensity curves (Fig 5). These
observations are similar to those of Wilke et al,15 who
studied pharmacologically vasodilated myocardium in which
LAD flow was reduced to various levels via a hydraulic occluder in
dogs, and to results reported by Manning et al,8 who
compared normal myocardium with regions distal to
angiographically occluded arteries in humans. In addition to regional
flow, however, other factors such as contrast
extravasation24 25 26 27
probably play an important role in the
initial slope of these time-intensity curves. More importantly,
however, since image intensity is derived from the proton signal rather
than from the contrast agent itself, image intensity may depend on the
number of water protons that are exposed to the agent and therefore on
the compartment (intravascular, interstitial, or cellular)
in which the agent is distributed. Recent studies by Wendland et
al28 and our group29 suggest that under
first-pass conditions, a limitation of myocardial water exchange,
most likely between the intravascular and interstitial
spaces, introduces a strong nonlinearity between myocardial contrast
concentration and image intensity in T1-weighted images.
Thus, although the initial slope of image intensity correlates with
flow, it is unclear whether this correlation is due to flow itself,
contrast extravasation, intercompartmental water exchange, or some
combination of these factors.
Contrary to the results of the initial
slopes of the image
time-intensity curves, the interpretation of myocardial enhancement
a few minutes after contrast administration may be less complex for
several reasons. First, the influence of
vascular-interstitial water exchange is probably less
important after the first pass because contrast concentrations are much
lower and change slowly over time.30 Under these
conditions, contrast concentration appears to be linearly related to
the change in 1/T1 in both blood31 and
myocardium.32 33 34 Second, the pulse
sequence
used in this study was specifically designed to produce a linear
relationship between image intensity and
1/T1,20 21 suggesting that our image
intensity data obtained after 2 minutes postcontrast (ie, well after
the first pass) are linearly related to contrast concentration. Third,
equilibrium between intravascular and interstitial contrast
concentrations most likely occurs much
faster24 25 27 than
the time required to clear the agent from the blood
pool.30 Thus, in normal myocardium it is
likely that after the initial transients that follow the bolus,
contrast concentrations in the intravascular and
interstitial spaces are essentially always equal to that of
the blood, and consequently the ratio of myocardial to blood contrast
concentrations would remain constant. This is precisely what was
observed experimentally in normal tissue, as shown in Fig 6
(MBSI is
constant over time).
Hyperenhancement
Infarct Size Versus Hyperenhancement
Our study is the first to compare infarct sizes with
hyperenhancement after 2 days of reperfusion. Several
investigators, however, have studied hyperenhancement of
myocardial tissue in acutely reperfused
infarcts.10 11 13 18 In
agreement with our findings (Fig 10), Saeed et
al18 showed that in rats subjected to 2
hours of occlusion followed by 3±0.5 hours of reperfusion, the spatial
extent of hyperenhanced regions in T1-weighted images
strongly correlates with the spatial extent of TTC-negative zones.
Schaeffer et al13 studied myocardial hyperenhancement in a
canine model of reperfused myocardial infarction and found that the
spatial extent of hyperenhancement was dependent on when the contrast
agent was administered after reperfusion. When the contrast agent was
administered early in the reperfusion period (5 minutes),
hyperenhancement correlated with the size of the risk region, whereas
when the contrast agent was administered later in the reperfusion
period (90 minutes), hyperenhanced regions were much smaller despite
similar infarct sizes.13
The finding that hyperenhanced regions closely correlate with TTC-negative regions and are only slightly (12%) larger is of potentially great importance because it strongly suggests that in infarcts reperfused for several days, as would be the case if the method of this paper was applied clinically, regions that become hyperenhanced several minutes after contrast administration are mostly nonviable. Consistent with this observation, we found, in another study, that in patients with reperfused infarcts examined within the first week, the subgroup of patients in whom the MBSI of hyperenhanced regions increased over time developed larger scars 6 months after infarct.35
Physiological Basis of
Hyperenhancement
Schaeffer et al13 measured myocardial
Gd-DTPA
concentrations postmortem with radiolabeled Gd and found higher Gd
concentrations in infarcted, reperfused canine myocardium
than in normal myocardium within 1 hour after
administration of contrast. This finding is consistent with the
results of Geschwind et al,36 who measured Gd-DTPA
concentrations using inductively coupled plasma mass spectroscopy
postmortem in rats and found higher Gd concentrations in infarcted,
reperfused myocardium. The results of these studies
strongly suggest that hyperenhancement of infarcted, reperfused
myocardium is at least in part due to higher Gd
concentrations.13
At least two mechanisms could explain
the increased contrast
concentrations in the hyperenhanced regions. First, the volume of
distribution for the contrast molecule within the voxel may increase.
This may be secondary to interstitial edema and/or eventual
disruption of the myocyte membrane after prolonged
ischemia,37 which may allow the contrast molecule
to enter the myocyte intracellular space. Second, the rate at which the
contrast molecule washes in and out of the myocardial tissue may be
slower in infarcted, reperfused regions. Our finding that image
intensity in the hyperenhanced regions did not change over time more
than 2 minutes after contrast (Fig 5B) supports the hypothesis
that
washout of the contrast molecule is impaired.
The MBSI (Fig
6) provides additional insight into these two potential
mechanisms. We found that in normal myocardium, the MBSI
remains constant over time, whereas the MBSI of the hyperenhanced
regions increased significantly over time. If the volume of
distribution for the contrast agent in hyperenhanced regions was
increased but contrast agent concentrations in the
interstitial space (and/or cell space) remained equal to
that of blood, the MBSI would shift to a higher level than that of
normal tissue but would remain constant over time. The observation that
the MBSI in hyperenhanced regions increases over time therefore
strongly suggests that the rapid communication between the
interstitial space and the blood space observed in normal
myocardium no longer exists in hyperenhanced regions.
Hypoenhancement
No-Reflow Size Versus Hypoenhancement
Although zones of hypoenhancement within infarcted
myocardium have been observed by other groups in the
absence of reperfusion,14 15 17 to our
knowledge the only
study documenting such hypoenhanced regions in reperfused infarcts is
our recent clinical study.16 Our finding that these
regions of hypoenhancement show a high degree of correlation with the
spatial location of the no-reflow zones by thioflavin (Fig 7)
provides strong evidence that hypoenhancement is related to the
no-reflow phenomenon described by us19 and
others.6 38 Consistent with previous observations,
we found that myocardial blood flow in thioflavin-negative regions
at the time of MR imaging (48 hours, Fig 3) was much lower than
in the
remote regions (0.37±0.09 versus 0.88±0.10 mL/min per 100 grams,
respectively, P<.001). This provides additional strong
evidence that hypoenhanced regions represent infarcted regions
with extremely low blood flow.
Physiological Basis of
Hypoenhancement
We found that before contrast administration, image
intensity in the hypoenhanced regions was not significantly lower than
intensity in the other two myocardial regions of interest (hypo,
17.1±1.6; hyper, 16.7±1.3; remote, 19.8±1.5;
P=NS). This
suggests that hypoenhancement is not due to some baseline abnormality
but rather is related to delayed contrast penetration in these regions.
Delayed contrast penetration might be explained by widespread
microvascular damage during the reperfusion period, a feature
characteristic of no-reflow regions.19 This widespread
microvascular damage decreases regional flow secondary to decreases in
functional capillary density. In addition, the decrease in functional
capillary density would result in a large increase in the time required
for the contrast molecule to diffuse into the extravascular space (on a
voxel scale) due to increased diffusion distances and the fact that
diffusion time increases with the square of distance.
In a previous study that used the same canine model of reperfused infarction as the present study, we compared thioflavin-negative with thioflavin-positive regions by light and electron microscopy.19 Thioflavin-negative regions exhibited widespread microvascular damage characterized by microvascular obstruction due to neutrophil plugging, microvascular thrombosis, endothelial cell swelling, extravascular compression by tissue edema, or a combination of these factors. Thioflavin-positive areas within the risk region demonstrated moderate tissue injury, with a mixture of coagulation and contraction band necrosis.19 Contraction band necrosis within thioflavin-negative regions was widespread after 3.5 hours of reperfusion19 but was not prominent after shorter reperfusion times,19 38 suggesting that in addition to "true" (ie, immediate) no-reflow found at the time of reperfusion, a substantial portion of postischemic myocardium undergoes progressive vascular obstruction during reperfusion. This suggests that the presence and spatial extent of no-reflow regions observed with MR may depend on postinfarct reperfusion times.
Summary
Although the presence of hypoenhanced and
hyperenhanced
regions is related to regional myocardial blood flow, other factors,
such as the rate of contrast clearance from the blood, the rate of
diffusion of the contrast molecule out of the vascular space, and the
functional capillary density, probably play important roles. Thus, the
regions of hypoenhancement and hyperenhancement observed in this study
appear to represent disruptions in the normal rapid diffusion
of the contrast molecule in and out of the myocardial interstitium.
These enhancement patterns might be better described as providing
information about the delivery of nutrients to cardiac myocytes rather
than perfusion through the microvasculature.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by the Frank T. McClure Fellowship in Cardiovascular Research (Dr Judd), NIH-NHLBI grant HL-17655 (Specialized Center of Research in Ischemic Heart Disease, Dr Becker), and NIH-NHLBI grant HL-45090 (Dr Zerhouni). The authors thank Anthony DiPaula for his work with the experimental preparation and data analysis, Kenneth Rent for his work with the MR imaging, and Ann Capriotti for the illustrations and figures.
Received February 7, 1995; revision received April 3, 1995; accepted April 21, 1995.
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References |
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G. K. Lund, A. Stork, M. Saeed, M. P. Bansmann, J. H. Gerken, V. Muller, J. Mester, C. B. Higgins, G. Adam, and T. Meinertz Acute Myocardial Infarction: Evaluation with First-Pass Enhancement and Delayed Enhancement MR Imaging Compared with 201Tl SPECT Imaging Radiology, July 1, 2004; 232(1): 49 - 57. [Abstract] [Full Text] [PDF]
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H. Abdel-Aty, A. Zagrosek, J. Schulz-Menger, A. J. Taylor, D. Messroghli, A. Kumar, M. Gross, R. Dietz, and M. G. Friedrich Delayed Enhancement and T2-Weighted Cardiovascular Magnetic Resonance Imaging Differentiate Acute From Chronic Myocardial Infarction Circulation, May 25, 2004; 109(20): 2411 - 2416. [Abstract] [Full Text] [PDF]
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E. Wellnhofer, A. Olariu, C. Klein, M. Grafe, A. Wahl, E. Fleck, and E. Nagel Magnetic Resonance Low-Dose Dobutamine Test Is Superior to Scar Quantification for the Prediction of Functional Recovery Circulation, May 11, 2004; 109(18): 2172 - 2174. [Abstract] [Full Text] [PDF]
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S.R. Underwood, J. J Bax, J. v. Dahl, M. Y Henein, A. C van Rossum, E. R Schwarz, J.-L. Vanoverschelde, E. E.v. d. Wall, and W. Wijns Imaging techniques for the assessment of myocardial hibernation: Report of a Study Group of the European Society of Cardiology Eur. Heart J., May 2, 2004; 25(10): 815 - 836. [Abstract] [Full Text] [PDF]
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 K. C. Wu and J. A.C. Lima Noninvasive Imaging of Myocardial Viability: Current Techniques and Future Developments Circ. Res., December 12, 2003; 93(12): 1146 - 1158. [Abstract] [Full Text] [PDF]
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A. M. Beek, H. P. Kuhl, O. Bondarenko, J. W. R. Twisk, M. B. M. Hofman, W. G. van Dockum, C. A. Visser, and A. C. van Rossum Delayed contrast-enhanced magnetic resonance imaging for the prediction of regional functional improvement after acute myocardial infarction J. Am. Coll. Cardiol., September 3, 2003; 42(5): 895 - 901. [Abstract] [Full Text] [PDF]
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J. Schulz-Menger, M. Gross, D. Messroghli, F. Uhlich, R. Dietz, and M. G. Friedrich Cardiovascular magnetic resonance ofacute myocardial infarction at a very early stage J. Am. Coll. Cardiol., August 6, 2003; 42(3): 513 - 518. [Abstract] [Full Text] [PDF]
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H. P. Kuhl, A. M. Beek, A. P. van der Weerdt, M. B. M. Hofman, C. A. Visser, A. A. Lammertsma, N. Heussen, F. C. Visser, and A. C. van Rossum Myocardial viability inchronic ischemic heart disease: Comparison of contrast-enhanced magnetic resonance imaging with 18F-fluorodeoxyglucose positron emission tomography J. Am. Coll. Cardiol., April 16, 2003; 41(8): 1341 - 1348. [Abstract] [Full Text] [PDF]
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C. R. Weiss, A. H. Aletras, J. F. London, J. L. Taylor, F. H. Epstein, R. Wassmuth, R. S. Balaban, and A. E. Arai Stunned, Infarcted, and Normal Myocardium in Dogs: Simultaneous Differentiation by Using Gadolinium-enhanced Cine MR Imaging with Magnetization Transfer Contrast Radiology, March 1, 2003; 226(3): 723 - 730. [Abstract] [Full Text] [PDF]
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S. S. Lee, H. W. Goo, S. B. Park, C. H. Lim, G. Gong, J. B. Seo, and T.-H. Lim MR Imaging of Reperfused Myocardial Infarction: Comparison of Necrosis-Specific and Intravascular Contrast Agents in a Cat Model Radiology, March 1, 2003; 226(3): 739 - 747. [Abstract] [Full Text] [PDF]
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R. Y. Kwong, A. E. Schussheim, S. Rekhraj, A. H. Aletras, N. Geller, J. Davis, T. F. Christian, R. S. Balaban, and A. E. Arai Detecting Acute Coronary Syndrome in the Emergency Department With Cardiac Magnetic Resonance Imaging Circulation, February 4, 2003; 107(4): 531 - 537. [Abstract] [Full Text] [PDF]
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 T. Reffelmann and R. A. Kloner Microvascular reperfusion injury: rapid expansion of anatomic no reflow during reperfusion in the rabbit Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1099 - H1107. [Abstract] [Full Text] [PDF]
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B. L. Gerber, J. Garot, D. A. Bluemke, K. C. Wu, and J. A.C. Lima Accuracy of Contrast-Enhanced Magnetic Resonance Imaging in Predicting Improvement of Regional Myocardial Function in Patients After Acute Myocardial Infarction Circulation, August 27, 2002; 106(9): 1083 - 1089. [Abstract] [Full Text] [PDF]
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J.o. Barkhausen, W. Ebert, J.o. F. Debatin, and H.-J. Weinmann Imaging of myocardial infarction: comparison of magnevist and gadophrin-3 in rabbits J. Am. Coll. Cardiol., April 17, 2002; 39(8): 1392 - 1398. [Abstract] [Full Text] [PDF]
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S. H. Rezkalla and R. A. Kloner No-Reflow Phenomenon Circulation, February 5, 2002; 105(5): 656 - 662. [Full Text] [PDF]
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J. J. W. Sandstede, T. Pabst, M. Beer, C. Lipke, K. Baurle, F. Butter, K. Harre, W. Kenn, W. Voelker, S. Neubauer, et al. Assessment of Myocardial Infarction in Humans with 23Na MR Imaging: Comparison with Cine MR Imaging and Delayed Contrast Enhancement Radiology, October 1, 2001; 221(1): 222 - 228. [Abstract] [Full Text] [PDF]
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B. L. Gerber, C. E. Rochitte, D. A. Bluemke, J. A. Melin, P. Crosille, L. C. Becker, and J. A.C. Lima Relation Between Gd-DTPA Contrast Enhancement and Regional Inotropic Response in the Periphery and Center of Myocardial Infarction Circulation, August 28, 2001; 104(9): 998 - 1004. [Abstract] [Full Text] [PDF]
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 S. B. Reeder, Y. P. Du, J. A. C. Lima, and D. A. Bluemke Advanced Cardiac MR Imaging of Ischemic Heart Disease RadioGraphics, July 1, 2001; 21(4): 1047 - 1074. [Abstract] [Full Text] [PDF]
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J C Nilsson, G Nielsen, B A Groenning, T Fritz-Hansen, L Sondergaard, G B Jensen, and H B W Larsson Sustained postinfarction myocardial oedema in humans visualised by magnetic resonance imaging Heart, June 1, 2001; 85(6): 639 - 642. [Abstract] [Full Text]
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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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O. P. Simonetti, R. J. Kim, D. S. Fieno, H. B. Hillenbrand, E. Wu, J. M. Bundy, J. P. Finn, and R. M. Judd An Improved MR Imaging Technique for the Visualization of Myocardial Infarction Radiology, January 1, 2001; 218(1): 215 - 223. [Abstract] [Full Text]
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C. M. Kramer, W. J. Rogers Jr., S. Mankad, T. M. Theobald, D. L. Pakstis, and Y.-L. Hu Contractile reserve and contrast uptake pattern by magnetic resonance imaging and functional recovery after reperfused myocardial infarction J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1835 - 1840. [Abstract] [Full Text] [PDF]
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D. S. Fieno, R. J. Kim, E.-L. Chen, J. W. Lomasney, F. J. Klocke, and R. M. Judd Contrast-enhanced magnetic resonance imaging of myocardium at risk: Distinction between reversible and irreversible injury throughout infarct healing J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1985 - 1991. [Abstract] [Full Text] [PDF]
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C. E. Rochitte, R. J. Kim, H. B. Hillenbrand, E.-l. Chen, and J. A. C. Lima Microvascular Integrity and the Time Course of Myocardial Sodium Accumulation After Acute Infarction Circ. Res., October 13, 2000; 87(8): 648 - 655. [Abstract] [Full Text] [PDF]
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 K. Rajappan, N. G. Bellenger, L. Anderson, and D. J. Pennell The role of cardiovascular magnetic resonance in heart failure Eur J Heart Fail, September 1, 2000; 2(3): 241 - 252. [Abstract] [Full Text] [PDF]
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J. Bremerich, M. Saeed, H. Arheden, C. B. Higgins, and M. F. Wendland Normal and Infarcted Myocardium: Differentiation with Cellular Uptake of Manganese at MR Imaging in a Rat Model Radiology, August 1, 2000; 216(2): 524 - 530. [Abstract] [Full Text]
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S. I. Choi, S. H. Choi, S. T. Kim, K. H. Lim, C. H. Lim, G. Y. Gong, H. Y. Kim, H.-J. Weinmann, and T.-H. Lim Irreversibly Damaged Myocardium at MR Imaging with a Necrotic Tissue-Specific Contrast Agent in a Cat Model Radiology, June 1, 2000; 215(3): 863 - 868. [Abstract] [Full Text]
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R. J. Kim, D. S. Fieno, T. B. Parrish, K. Harris, E.-L. Chen, O. Simonetti, J. Bundy, J. P. Finn, F. J. Klocke, and R. M. Judd Relationship of MRI Delayed Contrast Enhancement to Irreversible Injury, Infarct Age, and Contractile Function Circulation, November 9, 1999; 100(19): 1992 - 2002. [Abstract] [Full Text] [PDF]
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M. Saeed, J. Bremerich, M. F. Wendland, R. Wyttenbach, H.-J. Weinmann, and C. B. Higgins Reperfused Myocardial Infarction as Seen with Use of Necrosis-specific versus Standard Extracellular MR Contrast Media in Rats Radiology, October 1, 1999; 213(1): 247 - 257. [Abstract] [Full Text]
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L. J. M. Kroft, J. Doornbos, R. J. van der Geest, S. Benderbous, and A. de Roos Infarcted Myocardium in Pigs: MR Imaging Enhanced with Slow-Interstitial-Diffusion Gadolinium Compound P760 Radiology, August 1, 1999; 212(2): 467 - 473. [Abstract] [Full Text]
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R. J. Kim, R. M. Judd, E.-L. Chen, D. S. Fieno, T. B. Parrish, and J. A. C. Lima Relationship of Elevated 23Na Magnetic Resonance Image Intensity to Infarct Size After Acute Reperfused Myocardial Infarction Circulation, July 13, 1999; 100(2): 185 - 192. [Abstract] [Full Text] [PDF]
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W. J. Rogers Jr, C. M. Kramer, G. Geskin, Y.-L. Hu, T. M. Theobald, D. A. Vido, S. Petruolo, and N. Reichek Early Contrast-Enhanced MRI Predicts Late Functional Recovery After Reperfused Myocardial Infarction Circulation, February 16, 1999; 99(6): 744 - 750. [Abstract] [Full Text] [PDF]
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P. Croisille, C. C. Moore, R. M. Judd, J. A. C. Lima, M. Arai, E. R. McVeigh, L. C. Becker, and E. A. Zerhouni Differentiation of Viable and Nonviable Myocardium by the Use of Three-Dimensional Tagged MRI in 2-Day-Old Reperfused Canine Infarcts Circulation, January 19, 1999; 99(2): 284 - 291. [Abstract] [Full Text] [PDF]
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K. Ramani, R. M. Judd, T. A. Holly, T. B. Parrish, V. H. Rigolin, M. A. Parker, C. Callahan, S. W. Fitzgerald, R. O. Bonow, and F. J. Klocke Contrast Magnetic Resonance Imaging in the Assessment of Myocardial Viability in Patients With Stable Coronary Artery Disease and Left Ventricular Dysfunction Circulation, December 15, 1998; 98(24): 2687 - 2694. [Abstract] [Full Text] [PDF]
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K. C. Wu, R. J. Kim, D. A. Bluemke, C. E. Rochitte, E. A. Zerhouni, L. C. Becker, and J. A. C. Lima Quantification and time course of microvascular obstruction by contrast-enhanced echocardiography and magnetic resonance imaging following acute myocardial infarction and reperfusion J. Am. Coll. Cardiol., November 15, 1998; 32(6): 1756 - 1764. [Abstract] [Full Text] [PDF]
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C. E. Rochitte, J. A. C. Lima, D. A. Bluemke, S. B. Reeder, E. R. McVeigh, T. Furuta, L. C. Becker, and J. A. Melin Magnitude and Time Course of Microvascular Obstruction and Tissue Injury After Acute Myocardial Infarction Circulation, September 8, 1998; 98(10): 1006 - 1014. [Abstract] [Full Text] [PDF]
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K. C. Wu, E. A. Zerhouni, R. M. Judd, C. H. Lugo-Olivieri, L. A. Barouch, S. P. Schulman, R. S. Blumenthal, and J. A. C. Lima Prognostic Significance of Microvascular Obstruction by Magnetic Resonance Imaging in Patients With Acute Myocardial Infarction Circulation, March 3, 1998; 97(8): 765 - 772. [Abstract] [Full Text] [PDF]
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R. J. Kim, J. A. C. Lima, E.-L. Chen, S. B. Reeder, F. J. Klocke, E. A. Zerhouni, and R. M. Judd Fast 23Na Magnetic Resonance Imaging of Acute Reperfused Myocardial Infarction : Potential to Assess Myocardial Viability Circulation, April 1, 1997; 95(7): 1877 - 1885. [Abstract] [Full Text]
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R. J. Kim, E.-L. Chen, J. A.C. Lima, and R. M. Judd Myocardial Gd-DTPA Kinetics Determine MRI Contrast Enhancement and Reflect the Extent and Severity of Myocardial Injury After Acute Reperfused Infarction Circulation, December 15, 1996; 94(12): 3318 - 3326. [Abstract] [Full Text]
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