Delayed reduction of tissue water diffusion
after myocardial ischemia
EDWARD W. HSU,1 RONG XUE,1 ALEX HOLMES,1 AND JOHN R. FORDER2
Departments of 1Biomedical Engineering and 2Radiology, The Johns Hopkins
University School of Medicine, Baltimore, Maryland 21205-2195
magnetic resonance imaging; apparent diffusion coefficient;
myocardial infarction
DIFFUSION OF WATER is sensitive to changes in the
structural geometry and organization of its molecular
environment and can be noninvasively measured by
using nuclear magnetic resonance (MR) techniques via
the signal attenuation caused by the loss of spin-phase
coherence in the presence of magnetic field gradients
(30). The MR apparent diffusion coefficient (ADC) of
tissue water has been found to decrease dramatically
after acute cerebral ischemia (21). The ensuing research, the subject of several reviews (9, 11, 27, 32),
suggests that the rapid decrease and reversal of the
ADC change on recovery may offer the potential for
early, noninvasive detection of stroke and reliable
prediction of ischemic brain injury. The ADC decrease
has been associated with the depletion of cellular
energy stores (19), and cell swelling resulted from the
disruption of membrane electrochemical homeostasis
(3). Theoretical models of water diffusion in tissues (15,
29, 31) and direct measurements in single cells undergoing physiological perturbation (12) indicate that the
predominant biophysical factor underlying the ADC
decrease is the reduction of extracellular water volume
fraction during cell swelling (rather than changes in
the intrinsic diffusion characteristics of intra- and
extracellular water). The specificity of the ADC decrease to cell swelling, which is a common pathophysiological response in distressed tissues, has been extended to diffusion-weighted MR imaging studies of
other disorders such as cortical spreading depression
(5), status epilepticus (36), and acute renal failure (33).
MR techniques have long been used in the study of
ischemic heart diseases and, in general, have included
assessments of 1) myocardial metabolic activities using
MR spectroscopy (8, 34), 2) contractile function using
rapid imaging (23, 28) and MR tagging (2, 18) methods,
and 3) MR image intensity changes induced by endogenous relaxation mechanisms (17, 24) or exogenous
contrast agents (8, 26). Each of these approaches has its
unique advantages and drawbacks. For example, MR
spectroscopy may provide better specificity for pathophysiological responses but is limited in spatial and
temporal resolution because of the inherently low concentration of tissue metabolites. Although imaging
techniques based on mapping the distribution of water
molecules offer improved resolution, regional contractility measurements may not be effective in distinguishing viable but dysfunctional (e.g., stunned or hibernating) tissue from nonviable myocardium. On the other
hand, tissue viability and perfusion studies using exogenous contrast agents have been complicated by quantitation difficulties in relating image intensity to contrast
agent concentration in tissues.
Because of the complexity and heterogeneity of the
pathophysiology, proper assessments of ischemic myocardial injury may require not just one but several
examinations that are each sensitive to different responses in a comprehensive study. In this regard, tissue
diffusion changes may provide new insights regarding
the dynamics of myocardial injury and may complement established approaches in the study of ischemic
heart diseases. The goal of this study is thus to
determine whether tissue ADC changes occur after
regional myocardial ischemia in an isolated, perfused
rabbit heart model and whether diffusion changes can
be used to monitor the nature and evolution of tissue
injury.
MATERIALS AND METHODS
Isolated, perfused heart preparation. Hearts were obtained
from New Zealand White male rabbits and were perfused
retrogradely via the aorta using an MR-compatible Langendorff apparatus as described previously (1). Tissue and perfusate temperature were maintained at 37°C via a water-filled
heat-exchange circuit. The perfusate was continually equilibrated with a 95% O2-5% CO2 gas mixture. To avoid excess
hydrostatic pressure accumulation and distension of the left
ventricle (LV) resulting from thebesian drainage or aortic
valvular insufficiency, a thin (1 mm OD) polyethylene tube
was inserted into the LV through the mitral valve to serve as
a vent. The beating heart was perfused with a modified
Krebs-Henseleit (KH, pH 7.4) bicarbonate buffer containing
(in mM) 118.0 NaCl, 25.0 NaHCO3, 5.0 dextrose, 4.6 KCl, 2.5
0363-6135/98 $5.00 Copyright r 1998 the American Physiological Society
H697
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Hsu, Edward W., Rong Xue, Alex Holmes, and John R.
Forder. Delayed reduction of tissue water diffusion after
myocardial ischemia. Am. J. Physiol. 275 (Heart Circ. Physiol.
44): H697–H702, 1998.—The apparent diffusion coefficient
(ADC) of water after regional myocardial ischemia was
measured in isolated, perfused rabbit hearts by using magnetic resonance imaging (MRI) techniques. After ligation of
the left anterior descending coronary artery, the ADC of the
nonperfused region showed a gradual but significant decreasing trend over time, whereas that of the normally perfused
myocardium remained constant. Morphological analysis revealed that the ADC decrease reflected the expansion of a
subregion of reduced ADC within the nonperfused myocardium. The dynamics of the diffusion change and the morphological progression of the affected tissue suggest that the ADC
decrease may be linked to the onset of myocardial infarction,
which is known to involve myocyte swelling. The ADC reduction provides a potentially valuable MRI tissue-contrast
mechanism for noninvasively determining the viability of the
ischemic myocardium and assessing the dynamics of acute
myocardial infarction.
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REDUCTION OF WATER DIFFUSION AFTER MYOCARDIAL ISCHEMIA
Fig. 1. Effect of anisotropic myocardial fiber orientation on diffusion
measurement. Ventricular myocardium contains parallel fibers that
are characterized by transmural rotation of fiber angle. Because
diffusion is faster along fibers than across fibers, encoding diffusion
parallel to fiber planes (a) would produce a transmural variation in
the measured apparent diffusion coefficient (ADC). In contrast, the
epicardial-endocardial axis (b) is mostly perpendicular to fibers and
would thus yield a relatively uniform ADC.
extracellular ionic environment in the myocardium. Regional
ischemia was induced by permanently ligating (with a 4-O
silk suture) the left anterior descending coronary artery
(LAD) ,1 cm above the imaging plane. The heart was
arrested again, and multiple series of diffusion-weighted
images (4 images per series with same parameters as the
baseline images) were continuously acquired over a period of
2.5 h. At the conclusion of each experiment, gadoliniumdiethylenetriaminepentaacetic acid (Gd-DTPA), an MR contrast agent, was infused, and standard gradient echo images
(TE 30 ms, TR 150 ms) were obtained to independently
demarcate the nonperfused region. In all, five hearts were
included in this study.
Data analysis. ADC maps were generated for each series of
diffusion-weighted images via pixel-by-pixel nonlinear leastsquares fitting according to
I 5 I0 exp(2bD)
(1)
where I is the signal intensity, I0 is the diffusion-independent
signal intensity (including spin density and relaxation effects), and D is the ADC. The acquisition starting time for
each image series was assigned to be the time point (in min) of
the corresponding ADC map, with t 5 0 representing the
preocclusion time point. It is noted that the calculated
exponential decay constant (i.e., the ADC) based on images
acquired with constant TR and TE would be independent of
the longitudinal (T1 ) and transverse relaxation time (T2 )
contrast present in the individual images. Furthermore, the
ADC calculation implicitly assumed a monoexponential signal intensity decay as a function of diffusion weighting.
Because each signal intensity decay curve was sampled at
only four diffusion-weighting b values, no attempt was made
to examine changes in the nature of diffusion (e.g., mono-, bi-,
or complex exponential decay).
The least-diffusion-weighted image (which contained mostly
a mixed T1 and T2 contrast due to the relatively short TR and
long TE employed) of each series was used as a guide for
defining region-of-interest (ROI) templates. ROI templates
were generated for the ischemic and nonischemic LV (both on
the free wall) and the perfusate standard. Lacking anatomic
landmarks, the same nonischemic ROI template was used for
successive time points in each heart. In cases when the heart
moved between time points (as could happen between the two
epochs of cardioplegia, and subsequently when the ischemic
myocardium entered into contracture), the template was
redrawn so that approximately the same myocardial volume
was covered. In contrast, a separate ischemic ROI template
was generated for each time point from the region of reduced
intensity in the least-diffusion-weighted image. The assignment of the ischemic region was based on the observation that
the region was morphologically consistent with the nonperfused area demarcated by Gd-DTPA enhancement. The ischemic ROI template of the first postocclusion time point (t 5 10
min) was also used for the preocclusion (t 5 0) time point.
Mean ADC values were calculated over the ROI templates
and normalized to that of the perfusate standard at each time
point. The temporal trend of diffusion in each myocardial
region was determined, to a first approximation, by normalizing the ADC values to their respective preischemic values and
calculating the slope of the ADC as a function of time using
linear regression. To avoid unintentional bias associated with
subjective determination of the onset of decreased ADC,
linear regression was performed on the entire time course.
Individual slopes were then averaged among the five hearts
and compared with the zero-mean hypothesis using Student’s
t-test. A difference with P , 0.05 was considered to be
statistically significant.
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CaCl2, 1.2 KH2PO4, and 1.0 MgSO4. Because of the sensitivity
of diffusion-weighted MR images to bulk motion, the heart
was arrested before imaging. Cardiac arrest was induced and
maintained by perfusing with a cardioplegic solution [modified St. Thomas’ Hospital solution (35)] that consisted of (in
mM) 110.0 NaCl, 16.0 MgCl2, 16.0 KCl, 10.0 NaHCO3, 5.0
dextrose, and 1.2 CaCl2. Bovine serum albumin (BSA, 3%
wt/vol) was added to both perfusates to minimize interstitial
edema formation.
MR imaging. MR imaging experiments were conducted
using a General Electric 4.7-T Omega CSI instrument
equipped with shielded gradients (Accustar). The perfused
heart, together with a small sealed tube of perfusate standard
(to provide reference for the ADC), was placed inside a
31-mm-diameter loop-gap radio-frequency transmitter-receiver coil. On cardiac arrest (which occurred several minutes
after perfusion was switched to the cardioplegic solution), a
series of four baseline diffusion-weighted images [256 3 64
zero-filled to 256 3 256 matrix, 40-mm field of view, 4-mm
slice thickness, echo time (TE) 50 ms, repetition time (TR) 1 s,
and 2 averages] containing a short-axis view of the heart were
acquired using a standard spin-echo sequence, with diffusionweighting levels (or b-values) of 67, 266, 599, and 740 s/mm2.
In the first heart, diffusion was encoded in the phaseencoding direction. Because this encoding direction had a
component parallel to the myocardial fiber orientations in the
targeted ischemic myocardium, anisotropic diffusion and the
rotation of fibers caused noticeable, systematic transmural
variations in image intensity. This dependence of the ADC on
the diffusion-encoding direction and the myocardial fiber
orientation is schematically explained in Fig. 1. To reduce the
nonuniform anisotropic diffusion effects, we encoded diffusion
in the next four hearts in the readout direction, which was
mostly perpendicular to the regional myocardial fibers.
After the acquisition of baseline images, the perfusate was
switched back to normal KH buffer, and the heart was
permitted to beat for 10 min to allow restoration of a normal
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REDUCTION OF WATER DIFFUSION AFTER MYOCARDIAL ISCHEMIA
To measure the morphological progression of the ischemic
myocardium that showed reduced ADC, we selected a threshold on the ADC maps at 50% of the mean ADC of the perfusate
standard (i.e., pixels with higher ADC values were eliminated). The 50% threshold value was selected because the
ADC in the core of the ischemic regions decreased below,
while the nonischemic regions remained above, the threshold
at longer time points. The number of pixels within a contiguous region inside the hypoperfused LV wall was counted.
Because small, isolated areas were likely dominated by image
noise, contiguous areas of less than three pixels in size were
excluded from the tally. The total area was normalized to the
size of the corresponding ischemic LV ROI, and the morphological progression was characterized by performing leastsquares curve fitting of the percent area %P as a sigmoid
logistic function of time according to the general form
vf 2 vi
11
t
1t2
h
(2)
The fitted parameters vi, vf, h, and t corresponded to (for
negative h) the initial and final values of %P, the exponential
rate of change, and the linear time-compression factor, respectively. The function was chosen because the morphological
progression of tissue injury was found to be a sigmoid logistic
function (20); however, a different basis function was used in
the present study to better characterize slow changes in the
early postocclusion time points.
RESULTS
Representative images of an isolated, perfused heart
are shown in Fig. 2, including least-diffusion-weighted
images obtained before (A) and 10 min after LAD
occlusion (B), a Gd-DTPA-enhanced image (C), and a
corresponding ADC map at t 5 150 min (D). The images
contain a short-axis view of the heart in which the LV
appears as an annular-shaped region. The nonperfused
LV appears in the Gd-DTPA-enhanced image (Fig. 2C)
as a relatively bright area because the normally perfused myocardium has a shorter T2 from the presence of
high concentration of the contrast agent. The postocclusion image (Fig. 2B) contains an LV region that has
reduced signal intensity, and the region is morphologically similar to the hypoperfused zone demarcated in
Fig. 2C. On the other hand, the ADC map (Fig. 2D)
shows that the ADC within the hypoperfused LV has
decreased; however, the area of reduced ADC is smaller
than the hypoperfused region.
The calculated slopes of the ischemic and nonischemic ADC as functions of time are tabulated in Table 1.
The normalized ADC of the ischemic region shows a
statistically significant (P , 0.03) decreasing trend
over time, with an average slope of 21.38 6 0.20 3 1023
min21 (n 5 5, 6SE). In contrast, no significant trend
was found in the ADC of the nonischemic region (0.01 6
0.10 3 1023 min21 average slope, P . 0.8). The linear
regression results are summarized graphically in Fig. 3.
Individual results of the sigmoid logistic regression
describing the morphological progression of the ischemic ADC reduction are tabulated in Table 2. Figure 4
shows the average percent areas of reduced ADC and
the response reconstructed from averaged curve-fit
Fig. 2. Representative images of an ischemic heart. A–D contain
short-axis view of heart showing annular left ventricle (LV). Images
are least-diffusion-weighted spin-echo images obtained before (A)
and 10 min after ischemic insult (B), gadolinium-diethylenetriaminepentaacetic acid-enhanced gradient echo image that delineates hypoperfused LV as area of higher intensity (C), and calculated ADC
map (to be distinguished from a diffusion-weighted image) at 150 min
after left anterior descending coronary artery (LAD) occlusion,
containing a region of reduced ADC within the hypoperfused LV (D).
Circular object at top left of cross-sections is perfusate standard.
Images have been numerically scaled to enhance contrast.
parameters. The results indicate that the ischemic
myocardium showing reduced ADC appears after LAD
occlusion and gradually increases in size over time.
Extrapolating from the average curve-fit response, the
percent area of reduced ADC reaches %P 5 50 at
approximately t 5 130 min after LAD occlusion.
DISCUSSION
Comparison between the least-diffusion-weighted images before and immediately after LAD occlusion (Fig.
Table 1. Slopes of regional ADC as a function of time
after LAD occlusion
Slope, 31023 min21
Heart
Ischemic LV
Nonischemic LV
1
2
3
4
5
Mean 6 SE
22.045
21.612
21.194
20.933
21.107
21.38 6 0.20
P , 0.03
0.168
20.044
20.341
0.044
0.243
0.01 6 0.10
P . 0.8
Mean apparent diffusion coefficient (ADC) of each region was
normalized to respective perfusate standard and preischemic value,
and slope was determined by linear regression. P value is determined
by testing group average slope to zero-mean hypothesis using Student’s t
statistics. LAD, left anterior descending coronary artery. LV, left ventricle.
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%P 5 vi 1
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REDUCTION OF WATER DIFFUSION AFTER MYOCARDIAL ISCHEMIA
2, A and B, respectively) reveals a region of reduced
intensity in the LV of the postocclusion image. The
anatomic similarity between the region and the
nonperfused area demarcated by Gd-DTPA enhancement (Fig. 2C) indicates that the intensity reduction is
linked to the perfusion deficit (i.e., ischemia) in the
myocardium. Similar intensity changes after regional
myocardial ischemia were reported in a previous study
(6). Qualitatively, Fig. 3 indicates that the ADC of the
ischemic myocardium appears to remain constant initially, then steadily decreases after 60 min following
LAD occlusion. Although the linear regression analysis
cannot determine the transition time point in which the
ADC reduction begins and is likely to underestimate
the slope of the decrease, the decreasing trend of the
ADC of the ischemic LV was found to be significant
(Table 1). In contrast, the ADC of the nonischemic
myocardium remained unchanged over time. The morphological analysis summarized in Table 2 and Fig. 4
Table 2. Least-squares curve-fit parameters describing
morphological progression of ischemic myocardium
showing decreased ADC
Heart
vi
vf
h
t, min
1
2
3
4
5
Mean 6 SE
3.0
4.6
3.9
7.9
10.3
5.9 6 1.4
290
70
46
68
46
104 6 47
21.63
21.80
25.87
22.64
26.06
23.60 6 0.98
263
63
103
134
121
137 6 34
The area that showed ADC values lower than 50% of perfusate
ADC, as a percentage of the ischemic myocardium area (%P), is fitted
to Eq. 2 (see Data analysis). Parameters: vi and vf , initial and final
values of %P; h, exponential rate of change; t, linear timecompression factor.
Fig. 4. Progression of area within ischemic myocardium showing
decreased ADC. No. of pixels that showed ADC values ,50% of
perfusate ADC was measured and normalized to area of ischemic
myocardium. Data points and error bars represent average (n 5 5)
percent areas and 6SEs, respectively, at various time points. Response of each heart was curve-fitted to a sigmoid logistic function
(Eq. 2). Solid line represents response reconstructed from averaged
curve-fit parameters reported in Table 2.
indicates that the ADC decrease in ischemic myocardium reflects an expansion of the area that has reduced
ADC within the hypoperfused myocardium rather than
a uniform ADC decrease in the entire hypoperfused
tissue. These results, combined, suggest that the temporal and morphological progression of the ADC reduction
in the ischemic myocardium is a delayed and gradual
process.
The dynamics of the ADC decrease may reflect the
delayed myocyte swelling after myocardial ischemia.
Electron microscopic examination of cellular ultrastructure has revealed that little or no cell swelling occurs
during the reversible and early stages of irreversible
ischemic injury (13). Direct measurement of tissue
water and electrolyte content has found that the ischemic canine myocardium is capable of at least partial
cell volume regulation through anaerobic glycolysis
(14). The ability of myocytes to regulate cell volume is
lost after 60 min of ischemia following the onset of
irreversible injury (i.e., myocardial infarction). The
transition time point between reversible and irreversible cell damage is likely dependent on the severity of
ischemia, degree of collateral arterial flow, and the
animal species. Studies of dog hearts under total
ischemia have found evidence of irreversible damage as
early as 20–40 min after ischemic insult (14). However,
it has been reported that the jeopardized myocardium
can be salvaged by reperfusion as late as 3–6 h after
ischemia (25).
The delayed and gradual ADC decrease after myocardial ischemia is markedly different from the dramatic
change observed in cerebral ischemia. The ADC decrease in the brain has been found to take place within
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Fig. 3. ADC of ischemic and nonischemic myocardium as functions of
time after LAD occlusion. Each data point represents averaged ADC
(n 5 5) normalized to both mean ADC of water standard and the
preocclusion (t 5 0) value. Error bars represent 6SEs. Solid lines are
reconstructed from averaged parameters of individual linear regression reported in Table 1.
REDUCTION OF WATER DIFFUSION AFTER MYOCARDIAL ISCHEMIA
producing a considerable through-plane volume-averaging effect in the observed diffusion characteristics.
Nevertheless, the present study demonstrates the potential to noninvasively visualize morphological
progression of acute myocardial tissue injury through
alterations in the tissue ADC. The noninvasive approach is expected to have significant implications for
determining infarct size in assessing, for example, the
effectiveness of pharmacological protective agents in
reducing irreversible tissue injury. Conventional histological methods require the heart to be mechanically
sectioned and therefore preclude quantitation of the
infarct size in the same heart at different time points. A
noninvasive technique is advantageous because repeated measurements can be performed on the same
hearts at different time points. Not only does the
technique dramatically reduce the number of animals
that need to be killed [e.g., 29 animals were used by
Miura et al. (20) compared with 5 used in the present
study], but also repeated measurements provide improved statistical power by controlling for the heterogeneity in the responses among different animals.
In conclusion, the tissue ADC has been shown to
decrease after regional myocardial ischemia. The reduction reflects the expansion of a subregion of ischemic
myocardium that has decreased ADC. In contrast to
acute cerebral ischemia, ischemic ADC reduction in the
myocardium is a delayed and gradual process and
occurs subsequent to observable T1 and T2 contrast
changes. The temporal and morphological progression
of the ADC reduction suggests that the diffusion change
may be related to the onset of myocardial infarction,
which is known to involve myocyte swelling. These
findings are promising for using the ADC reduction as
an MR imaging tissue-contrast mechanism to noninvasively determine the viability of the ischemic myocardium and to assess the dynamics of acute myocardial
infarction.
The authors gratefully acknowledge the advice and support of Dr.
S. Blackband.
This work was supported by an Independent Investigator Grant
from the Whitaker Foundation (J. R. Forder). E. W. Hsu was
supported by a Howard Hughes Predoctoral Fellowship.
Present address for E. W. Hsu: Center for In Vivo Microscopy, Duke
Univ. Medical Center, DUMC Box 3302, Durham, NC 22710.
Address for reprint requests: J. R. Forder, Div. of NMR Research,
Dept. of Radiology and Radiological Sciences, Johns Hopkins Univ.
School of Medicine, 217 Traylor Bldg., 720 Rutland Ave., Baltimore,
MD 21205-2195.
Received 15 July 1997; accepted in final form 16 April 1998.
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