JOURNAL OF MAGNETIC RESONANCE IMAGING 19:758 –770 (2004)
Invited Review
Analysis of Myocardial Perfusion MRI
Michael Jerosch-Herold, PhD,2* Ravi Teja Seethamraju, PhD,1 Cory M. Swingen, MSc,1
Norbert M. Wilke, MD,1 and Arthur E. Stillman, MD, PhD1
Rapid MR imaging (MRI) during the first pass of an injected
tracer is used to assess myocardial perfusion with a spatial
resolution of 2–3 mm, and to detect any regional impair-
ments of myocardial blood flow (MBF) that may lead to
ischemia. The spatial resolution is sufficient to detect flow
reductions that are limited to the subendocardial layer. The
capacity of the coronary system to increase MBF several-
fold in response to vasodilation can be quantified by anal-
ysis of the myocardial contrast enhancement. The myocar-
dial perfusion reserve (MPR) is a useful concept for
quantifying the vasodilator response. The perfusion reserve
can be estimated from the ratio of MBFs during vasodila-
tion and at baseline, in units identical to those used for
invasive measurements with labeled microspheres, or from
dimensionless flow indices normalized by their value for
autoregulated flow at rest. The perfusion reserve can be
reduced as a result of a blunted hyperemic response
and/or an abnormal resting blood flow. The absolute quan-
tification of MBF removes uncertainties in the evaluation of
the vasodilator response, and can be achieved without the
use of complex tracer kinetic models; therefore, its appli-
cation to clinical studies is feasible.
Key Words: magnetic resonance imaging; myocardial
blood flow; tracer kinetics; perfusion; coronary artery dis-
ease
J. Magn. Reson. Imaging 2004;19:758 –770.
© 2004 Wiley-Liss, Inc.
MYOCARDIAL PERFUSION imaging affords a unique
view of the microcirculation, which only over the last
decade has received the attention it deserves in the
study of heart disease. Many of the adaptive processes
that take place in the presence of myocardial ischemia,
1
Department of Radiology, University of Minnesota, Minneapolis, Min-
nesota.
2
Advanced Imaging Research Center, Oregon Health and Science Uni-
versity, Portland, Oregon.
Contract grant sponsor: National Heart, Lung and Blood Institute (NIH/
NHLBI); Contract grant numbers: R01 HL65394-01; R01 HL65580-01;
Contract grant sponsor: Whitaker Foundation.
Norbert Wilke is now at the Cardiovascular Center, University of Florida
Health Science Center, Jacksonville, Florida.
Arthur E. Stillman is now at the Division of Radiology, Cleveland Clinic
Foundation, Cleveland, Ohio.
*Address reprint requests to: M.J.-H., Advanced Imaging Research
Center, Mayo Mail Code L452, 3181 SW Sam Jackson Park Road,
Portland, OR. E-mail: jeros001@umn.edu
Received August 1, 2003; Accepted February 24, 2004.
DOI 10.1002/jmri.20065
Published online in Wiley InterScience (www.interscience.wiley.com).
© 2004 Wiley-Liss, Inc.
such as myocardial angiogenesis (1), occur mostly at
the level of the myocardial microcirculation. Magnetic
resonance imaging (MRI) is increasingly being applied
as an alternative to nuclear medicine for assessing the
microcirculation (2– 4). Although there exist numerous
approaches to evaluate myocardial perfusion with MRI,
the use of contrast agents as tracers remains the most
robust method to image myocardial perfusion with MR.
In principle, this approach is similar to the use of trac-
ers in nuclear medicine; however, the detection of the
MRI contrast agent, the kinetics of myocardial contrast
enhancement during the first pass, and the analysis of
MRI perfusion studies each merit substantial effort to
fully explore the potential of this relatively new modality
for myocardial perfusion imaging.
The focus of this article is the analysis of myocardial
perfusion studies performed with rapid T1-weighted
MRI during the first pass of an injected contrast agent.
Myocardial contrast enhancement during the first pass
is sensitive to the level of myocardial blood flow, or
myocardial perfusion. The term “myocardial perfusion”
refers to blood flow in myocardial tissue through the
coronary arterial network, from the epicardial arteries,
through the arterioles (10 –100 ␮m diameter), down to
the capillaries, and through the venous network. In-
stead of describing blood flow through this complex
vascular network in terms of flow velocities in individ-
ual vessels, it is more appropriate to characterize the
blood flow in myocardial tissue by the amount of a
labeled substance that can traverse a unit volume of
tissue per unit time (5).
IMAGE ANALYSIS
MR myocardial perfusion scans that cover the first pass
of the injected contrast material typically comprise ap-
proximately 40 – 60 images for each slice location. The
cardiac contraction appears to be frozen, since the ac-
quisition time for each image should be short (on the
time scale of a heartbeat), and the image acquisition is
synchronized to the heart cycle by use of the R-wave on
the ECG as a trigger signal for the scanner. Breathing
should be suspended for at least part of the perfusion
scan to facilitate the interpretation and analysis of the
images, and avoid errors due to a shift of the slice
position relative to the heart.
Analyses of myocardial contrast enhancement can be
performed for each pixel within the endocardial and
758
Analysis of Myocardial Perfusion MRI
Figure 1. A T1-weighted gradient-echo image in the short-
axis view is shown with user-traced endo- and epicardial con-
tours, and ROIs in the center of the LV and RV cavities. The LV
wall was subdivided into eight transmural myocardial seg-
ments that are arranged in circumferential order, starting at
the anterior junction of the RV and LV, which serves here as an
anatomical landmark. Numbering the myocardial segments of
equal circumferential extent is a simple means of registering
the myocardial sectors with respect to an anatomical land-
mark.
epicardial border, or by subdividing the myocardium
circumferentially into sectors. A pixel-based analysis
takes full advantage of the underlying spatial resolution
of the images, but it requires accurate image registra-
tion to maintain a true spatial resolution on the order of
the pixel size, and often suffers from a poor contrast-
to-noise ratio (CNR). To address the latter shortcoming,
one can group pixels in the myocardium into regions of
interest (ROIs). The ROIs should be adapted to the car-
diac anatomy. The perfusion images are segmented
along the endo- and epicardial borders. For short-axis
views of the heart, the myocardium is then subdivided
into sectors that are arranged in circumferential order.
The location of the sectors can be registered to an easily
identifiable anatomical landmark, such as the anterior
junction of the left (LV) and right (RV) ventricles marked
in Fig. 1. The myocardial sectors generally have equal
circumferential extent, which is based, for example, on
the length of a centerline between the endo- and epi-
cardial borders. Any in-plane displacement of the heart
due to breathing motion during a perfusion study is
taken into account based on the endo- and epicardial
segmentation contours, and the marked position of an
anatomical landmark. Nevertheless, breathing motion
can also cause misregistration of the slice position per-
pendicular to the image plane, and breathing should
therefore be suspended at least for the relatively short
period that covers the wash-in of contrast agent.
Tracing the endo- and epicardial contours on each
image is a tedious and time-consuming process, which
759
remains the primary bottleneck of the analysis. It has
proven difficult to automate the segmentation of perfu-
sion images. The endocardial border is poorly defined
before the contrast material appears in the LV cavity,
and the subsequent very high contrast enhancement in
the cavity, in combination with suboptimal spatial res-
olution, may cause spill-over or partial volume effects in
pixels along the endocardial border. One may therefore
want to offset the traced endocardial border from the
cavity edges to avoid effects such as signal spillover due
to the limited number of phase encodings, and the nar-
row, transitory, dark banding artifact that can appear
at the endocardial border during peak contrast en-
hancement in the LV cavity.
Signal intensity (SI) curves depict the variation of the
SI in one pixel, or a group of pixels, over a set of images
acquired in series—typically with a time increment that
equals one or two R-to-R intervals. By recording the
heart rate or, better yet, the time at which each image is
acquired, one can generate an SI vs. time curve. Vari-
ous parameters are computed from these curves and
used in the evaluation of myocardial perfusion. A typi-
cal time-intensity curve and some of its characteristic
features are shown in Fig. 2.
An important parameter for the evaluation of SI
curves, and for quality control, is the peak CNR, which
is defined as the ratio of the observed SI change from
baseline to peak, divided by the standard deviation (SD)
of the SI before contrast enhancement:
Figure 2. An SI curve for a myocardial sector in the lateral
wall. Each data point (round circles) represents the mean SI
measured in the images for the user-defined myocardial sec-
tor. The images were acquired with a fast, T1-weighted, gradi-
ent-echo sequence during injection of a 0.04 mmol/kg bolus of
the Gd-DTPA, an extracellular MR contrast agent. The gray
curve represents the best fit of the gamma-variate function to
part of the experimental data, covering the range indicated by
the vertical arrows. The gamma-variate function can only be
used to fit the portion of the tissue curve corresponding to the
first pass of the contrast agent. The end of the first pass and
the appearance of the recirculation component can be best
ascertained from the SI changes observed in the blood pool.
Semiquantitative perfusion parameters, such as the slope,
and the peak SI are also illustrated.
760
Figure 3. The CNR was determined for a range of myocardial
ROI sizes. First, an anterior myocardial segment was outlined
on a perfusion image, and a pixel was chosen at random within
this user-traced border as a seed to grow an ROI by adding
nearest neighbors at random. At each stage of the region dila-
tion process, an SI curve was generated from all 50 images
comprising the perfusion scan to calculate the peak CNR of the
resulting SI curve. Random placement of the initial seed, and
region growing, were repeated 64 times. The CNR values
shown in the graph are averages over these 64 iterations. In
this example, a human volunteer held his breath for the entire
duration of the perfusion scan with a rapid T1-weighted, gra-
dient-echo sequence. Also shown (solid line) is a linear regres-
sion line fit on a log-log scale, and (dotted line) the case in
which CNR is assumed to be proportional to the square root of
the number of pixels in the ROI.
SI(peak) ⫺ SI(baseline)
C/N ⫽ (1)
STDEV(baseline)
The CNR depends on the contrast agent dosage, the
size of the ROI used to generate the SI curves, and the
pulse sequence parameters (e.g., the flip angle), among
other factors. If the SI noise in each pixel of a myocar-
dial tissue region could be modeled as white Gaussian
noise, then one would expect the CNR to increase in
proportion to N1/2, where N represents the number of
pixels in the given ROI. Figure 3 shows the variation of
the CNR as a function of the number of pixels in a
user-defined myocardial ROI, which follows a power-
law relationship. The observed increase of CNR fell be-
low the prediction of an increase proportional to N1/2,
which suggests that noise in adjacent pixels is not un-
correlated, and is not necessarily random. Possible
sources of SI variation that can give rise to correlated
signal fluctuations in adjacent pixels are cardiac and
breathing motion, even if only on the order of a few
pixels, and variations in the heart rate. Nevertheless, it
is crucial to group pixels into ROIs to obtain SI curves
Jerosch-Herold et al.
that are suitable for further analysis, which in practice
means achieving CNR ratios higher than roughly 10:1.
The use of surface coils in myocardial perfusion studies
entails that the sensitivity profile is not uniform over
the volume of the heart, as can be seen in Fig. 4. With
the use of newer parallel imaging techniques, such as
simultaneous acquisition of spatial harmonics
(SMASH) (6) or sensitivity encoding (SENSE) (7), the
images are automatically corrected for the sensitivity
profile of the surface coil elements. If this is not the
case, one must scale the SI curves for different myocar-
dial segments to correct for the SI heterogeneity that is
introduced by the use of surface coils. A simple way to
accomplish this is to assume that the receiver coil pro-
file varies linearly with distance, an approximation that
is reasonable for small distances, as shown in Fig. 4.
The SI curves for myocardial ROIs can then be scaled
relative to an ROI in the center of the LV, the latter being
used to measure an arterial input function. The scaling
factors are given by the ratio of the mean baseline SI in
a sector, divided by the baseline SI, averaged over all
sectors. It is assumed that before contrast enhance-
ment, T1 and other relevant tissue properties are equal
in all of the myocardial sectors (i.e., the myocardial SI
should be uniform if a body coil with a homogenous
receiver profile over the volume of the heart is used).
Alternatively, one can acquire two images with the
same sequence parameters, but with the use of a body
coil and a cardiac surface coil, respectively. The ratio of
these two images shows the variation of the receiver coil
profile, as shown in Fig. 4, and can be used to scale the
SI curves.
Improvements of the CNR by the use of higher con-
trast-agent dosages are limited by the requirement for
quantitative perfusion studies to maintain an approxi-
mately linear relationship between the SI and the con-
trast-agent concentration, which is only maintained
with low contrast-agent concentrations. To circumvent
this limitation, Christian et al (8) recently introduced a
double-bolus injection technique that allows measure-
ment of the input function with a low-dosage contrast
injection, followed by measurement of the myocardial
contrast enhancement with a higher-dosage bolus. It is
useful in this context to recall that the peak concentra-
tion of contrast agents in tissue is reduced in compar-
ison to the peak concentration seen in the LV, due to
the dispersion of the bolus during transit through the
epicardial vessels and the myocardial tissue. It is there-
fore the measurement of the arterial input that sets the
upper limit for the contrast-agent dosage, unless a dou-
ble-bolus injection technique is used to deal with the
linearity requirements for arterial and myocardial con-
trast enhancement separately.
In tissue, water exchange between the vascular and
interstitial spaces can alter the relationship between
the SI and the contrast agent concentration, which can
introduce substantial additional complexity into anal-
yses of myocardial contrast enhancement. However,
the effects of water exchange on myocardial contrast
enhancement can be mitigated with T1-weighted gradi-
ent-echo sequences by adjusting the pulse sequence
parameters (9).
Analysis of Myocardial Perfusion MRI 761

Figure 4. We calculated the image on the left side by taking the ratio of two MR images acquired with a surface and a body coil,
respectively. The ratio image was normalized such that the ratio equaled 100 in the center of the LV cavity. The light gray,
semitransparent horizontal bar denotes the location and direction of a profile cut, which is shown in the graph at right. The gray
line in the graph on the right indicates the extent of the heart on the graph. The variation of the SI ratio between the septal and
lateral walls is approximately 40%. This variation in the SI ratio is due to the drop-off of the receiver coil sensitivity with distance
from the surface coil placed on the anterior wall of a pig. SI variations introduced by the use of a surface coil must be corrected
for to avoid errors in the assessment of myocardial perfusion.

Aside from using higher dosages of contrast agent,
one can also increase the CNR by acquiring the image
during steady-state free precession (SSFP), after a sat-
uration-recovery magnetization preparation (10,11). In
our experience, the SSFP technique results in more
transient magnetic susceptibility artifacts during the
appearance of the contrast agent in the LV cavity com-
pared to spoiled gradient-echo techniques such as
turbo fast low-angle shot (FLASH) imaging. However,
further discussion regarding newer MR perfusion imag-
ing techniques, such as SSFP imaging, or very fast
echo-planar techniques is beyond the scope of this re-
view.
Assessment of Endo- and Epimyocardial Perfusion
With First-Pass MRI
High spatial resolution allows a separate assessment of
perfusion in the endo-and epicardial layers. Research
on coronary anatomy and physiology has firmly estab-
lished that the increased cardiac workload on the en-
docardial layer (as compared to the epicardial layer) is
matched by a transmural blood flow gradient (12). The
ratio of endo- and epicardial blood flow under normal
conditions is ⬎1:1. The transmural blood flow gradient
is quite sensitive to the presence of an epicardial coro-
nary artery stenosis, and an abnormal transmural
blood flow gradient is a marker of coronary disease (13).
The spatial resolution of MRI offers researchers a
unique opportunity to investigate blood flow in the sub-
endocardial layer. Mühling et al (14) showed that heart
transplant patients with detectable myocardial hyper-
trophy or prior rejection episodes have, at rest, a re-
duced endo-/epimyocardial perfusion ratio compared
to healthy volunteers or healthy transplant recipients.
One can subdivide the transmural myocardial sectors
into endo- and epicardial layers to assess the transmu-
ral blood flow gradient. In most cases, the dividing line
between subsectors is chosen to fall in the middle of the
transmural sector. The analysis works best for perfu-
sion images acquired at end-systole.
Myocardial Perfusion and the Cardiac Cycle
With current contrast-enhanced myocardial perfusion
techniques, different slices are imaged during different
phases of the cardiac cycle. For a quantitative analysis,
this raises the question of whether the results for dif-
ferent slices would reflect variations in coronary and
myocardial blood flow over the cardiac cycle (15). A
temporal resolution corresponding to one R-to-R inter-
val is necessary for assessments of myocardial blood
flow during maximal vasodilation (16). With T1-
weighted, gradient-echo sequences with a short echo
time (TE) and a non–slice-selective saturation-recovery
preparation, the measured myocardial contrast en-
hancement, normalized relative to the contrast en-
hancement in the LV cavity, appears to be independent
of the cardiac phase and flow variations in the ventric-
ular cavity. The results in Fig. 6 are consistent with the
notion that the contrast enhancement measured with a
temporal resolution of one R-to-R interval, or a multiple
762 Jerosch-Herold et al.

Figure 5. Perfusion images acquired in a normal volunteer at three phases during each heartbeat with a gradient-echo
technique with non-slice-selective saturation-recovery magnetization preparation. The central k-space lines for each image were
acquired at 110, 310, and 510 ms, respectively, after the R-wave was detected on the ECG trace. In the left panel are shown three
signal curves for the same anterior myocardial ROI location, but corresponding to three different phases of the cardiac cycle. In
the panel at right are shown the corresponding input functions from an ROI in the LV for the same three cardiac phases as in
the panel at left. The data points for the three cardiac phases nearly coincide, although inflow in the LV varies markedly during
the cardiac cycle. The R-to-R duration was 750 ms. Blood flows were determined from these signal curves, and blood flow values
differed by ⬍3%.

thereof, reflects the mean blood flow. Microspheres
deposition in tissue similarly reflects mean blood flow
(17). Figure 5 illustrates the good agreement of the
myocardial contrast enhancement patterns measured
during different phases of the cardiac cycle. The cardiac
phase that is used for the acquisition of perfusion im-
ages can therefore be chosen on the basis of other
considerations, such as maximizing the cross-sectional
thickness of the myocardium to increase the size of the
myocardial sectors and facilitate an analysis of endo-
and epicardial perfusion.
SEMIQUANTITATIVE ANALYSIS
The parameters of the SI curve illustrated in Fig. 2
generally do not have well-defined units. Any knowl-
edge about a relationship between a parameter and the
tissue blood flow is based mostly on empirical observa-
tions. An analysis based on these parameters is there-
fore considered to be semiquantitative. The parameters
that are commonly used for a semiquantitative assess-
ment of myocardial perfusion include the following:
Peak SI: The peak value of SI attained during the first
pass of the contrast agent, relative to its level before
contrast enhancement. A related parameter is the
contrast enhancement in percent, calculated from
the peak SI, divided by the average SI before the
onset of contrast enhancement.
Up-slope parameter: An approximation to the first
derivative of the SI curve during the initial ascent of
the first pass (i.e., the rate of change of the SI). The
rate of contrast enhancement in myocardial tissue
is often normalized by the rate of contrast enhance-
ment in the LV cavity.
Time to peak: The time from the onset of contrast
enhancement (referred to as the foot of the SI curve)
to the peak of the SI curve.
Mean transit time: The average time required for a
tracer to pass through the ROI.
Area under the SI curve: The area under the SI curve
from the foot to a user-defined point, such as the
time at which the SI peaks during the first pass.
Of the above parameters, the up-slope has been most
widely adapted for semiquantitative analyses of myo-
cardial perfusion (3,4,18 –20). To determine the up-
slope of the SI curve, one must obtain a smooth fit to the
SI data (e.g., by performing a least-squares fit of a func-
tion that approximates the shape of the first-pass
curves). A possible choice for this purpose is the Gam-
ma-variate function (21,22), which is described by the
following formula:
g共t兲 ⫽ 再 A 䡠 共t ⫺ t
foot
0 for t ⬍ tfoot
兲a 䡠 exp关 ⫺ 共t ⫺ tfoot兲/␶兴 for t ⱖ tfoot (2)
Figure 2 shows an example of an SI curve and its
Gamma-variate fit. The parameter tfoot in Eq. [2] repre-
sents the foot of the curve, where the signal starts to
rise above the baseline signal. Before optimizing the
adjustable parameters in Eq. [2], the user may want to
set the value of tfoot, as this tends to render the optimi-
zation of the remaining curve parameters more robust.
A Levenberg-Marquardt algorithm can be used for non-
linear least-squares fitting and optimization of the re-
maining parameters, namely A (amplitude), a (expo-
nent), and ␶. The recirculation component of the tissue
curves has to be excluded for the determination of the
fitting parameters, and for tissue curves the cut-off
point before the appearance of recirculating contrast
Analysis of Myocardial Perfusion MRI
Figure 6. The top panel shows the variation of the SI in the
center of the LV (open circles) during the first pass of Gd-DTPA
bolus through the LV in a patient with normal cardiac func-
tion. Shown as solid line is a model tissue residue curve,
simulated with a spatially distributed, multiple-path tracer
kinetic model (MMID4, National Simulation Resource, Univer-
sity of Washington, Seattle) for a flow of 1 mL/minute/g of
myocardial tissue, and a capillary permeability surface area
product of PS ⫽ 1 mL/minute/g. The bottom panel indicates
the sensitivity of the tissue residue curve to changes in blood
flow (F) and the capillary permeability surface area product
(PS). The sensitivity function was calculated as a partial deriv-
ative of the SI (S) with respect to the model parameter: ⳵S/⳵P,
where P stands for the model parameters F or PS, respectively.
The model parameter PS controls the leakage of contrast agent
from the vascular to the interstitial space. The sensitivity func-
tion for flow peaks during the wash-in of the contrast agent,
while the sensitivity to changes in the capillary permeability
becomes noticeable only after the first pass.
agent is best chosen by inspection of the arterial input.
The two vertical arrows in Fig. 2 represent the part
chosen for curve fitting. The left arrow was positioned at
the foot of the SI curve, to set tfoot.
The up-slope parameter has been used to compare
the level of contrast enhancement in different myocar-
dial sectors during the same injection, as well as to
compare contrast enhancement during maximal vaso-
dilation with its level at baseline (3,4,18,19). The up-
slope parameter reflects the rate of contrast enhance-
ment during the phase of the study when the measured
SI curve is most sensitive to differences in myocardial
blood flow, as shown by the sensitivity plots in Fig. 6.
For example, in a patient with single-vessel disease, the
up-slope in the territory of the epicardial vessel with a
lesion would be lower than in a remote region, particu-
763
larly for contrast enhancement during maximal vasodi-
lation. Up-slope values for the same myocardial region
can also be compared between “rest” and “stress” stud-
ies. The up-slope of a myocardial SI curve reflects the
level of regional perfusion, but it also changes in re-
sponse to the arterial input. Because of the hemody-
namic changes that occur with vasodilation, one must
take into account any differences in the arterial inputs
for rest and stress measurements to estimate a perfu-
sion reserve from up-slope values. Several investigators
have chosen to normalize the up-slope values for the
myocardial contrast enhancement with the up-slope
value for contrast enhancement in the blood pool
(3,4,18,19,23).
CENTRAL VOLUME PRINCIPLE
The central volume principle, which was originally in-
troduced by Zierler (24,25), provides a useful and ele-
gant theoretical basis for the quantitative, model-inde-
pendent analysis of perfusion. An ROI is assumed to
have a single input and a single output. The injection of
a tracer is described here by the variation of tracer
concentration at the (arterial) input cin(t). The blood flow
through the tissue region carries tracer to the output,
and the variation of the tracer at the output is denoted
by cout(t). The amount of tracer that remains in the
tissue region at any time t, q(t), represents the differ-
ence between the amount supplied to the tissue region
up to time t, and the total amount of tracer that has
exited the ROI up to the time t:
冕
t
q共t兲 ⫽ F 关c in 共s兲 ⫺ c out 共s兲兴 䡠 dt. (3)
0
where F is the tissue flow rate (e.g., in units of milliliters
per minute per gram of tissue).
Zierler (24,25) showed that if the transport within a
tissue ROI is assumed to be linear and stationary, then
the response to an arbitrary arterial input is given by
the convolution integral of this input with the tissue
impulse response:
q共t兲 ⫽ 冕
0
t
c in 共t ⫺ ␶兲 䡠 R共␶兲d␶. (4)
We denote the impulse response by R(t). The response
in a tissue region to an impulse input, the tissue im-
pulse response, has the useful property that its initial
amplitude equals the myocardial blood flow through
that region. This can be derived by considering Eq. [3]
for the special case when the input is a Dirac delta
impulse, cin(t) ⫽ ␦(t):
q共t兲 ⫽ F 冕 0
t
共␦共s兲 ⫺ c out 共s兲兲ds ⬅ R共t兲. (5)
We normally specify the input function such that
cin(t ⬍ 0) ⫽ 0. For finite flow rates, we require that cout(t ⫽
764
0) ⫽ 0, which means that the tracer can not instanta-
neously reach the output after injection. From Eq. [5], it
then follows that R(t ⫽ 0) ⫽ F, i.e., the initial amplitude
of the impulse response is equal to the flow rate F. This
property of the impulse response is independent of the
vascular and compartmental structure inside the tis-
sue ROI, or the properties of barriers (such as their
permeability). For example, leakage of a contrast agent
from the capillaries into the interstitial space produces
a redistribution of the contrast agent within the ROI,
but it does not contribute to flow in and out of the ROI
as long as transport by diffusion and convection is
much slower than by blood flow. For an MR contrast
agent such as Gd-DTPA, these assumptions hold up
well.
The central volume principle, when applied to the
case where the transit of tracer is monitored by imaging
of the heart, indicates that the blood flow can be deter-
mined by deconvolution of the measured tissue residue
curve with the arterial input curve, without the use of
any specific model for the transport or redistribution of
tracer within the tissue ROI. The model-independent
deconvolution analysis is very sensitive to noise in the
data. Deconvolution can give results that fit the ob-
served data but represent physiologically unrealistic
impulse responses. Therefore, one must constrain the
deconvolution operation. If the impulse response, R(t),
is measured at the input to the ROI, then R(t) should be
a monotonically decaying function of time, since, by
definition of the impulse input, no additional tracer
enters the tissue region after the initial Delta function
input. Furthermore, the impulse response should be
reasonably smooth. Smoothness of the impulse re-
sponse follows to the degree that the magnitudes of
flow, diffusion, and permeation in the heart establish
time scales that exclude abrupt SI changes in myocar-
dial tissue after contrast agent injection.
We have applied the Fermi function as an empirical
model for the impulse response (2,26). The Fermi model
of the impulse response has the following equation:
A models, such as the MMID4 model from the National
R共t兲 ⫽ , (6)
1 ⫹ exp[⫺共t ⫺ w兲/␶]
where A, w, and ␶ are the model parameters. The shape
of the Fermi function provides a reasonable approxima-
tion to the shape of the impulse response of an intra-
vascular tracer (27). The portion of the SI curves up to
the first-pass peak has higher sensitivity to flow
changes compared to later phases of the contrast en-
hancement, and the early enhancement is relatively
insensitive to capillary leakage of contrast agent (28).
This part of the SI curve can be approximated well by
the Fermi-function model to assess blood flow. The
Fermi model has only three adjustable parameters that
can be easily optimized to fit the observed data and
determine myocardial blood flow. The parameters A, w,
and ␶ of the Fermi function bear no direct relationship
to any physiological parameters of the myocardial mi-
crocirculation. We have validated the use of the Fermi
model for the quantification of myocardial perfusion
and the perfusion reserve by comparing it to blood flow
Jerosch-Herold et al.
measurements obtained with labeled microspheres
(29), and to invasive coronary flow reserve measure-
ments (2).
One can also analyze myocardial contrast enhance-
ment by building models that approximate the internal
architecture of the myocardial microcirculation. For a
model with adequate realism, one can define model
parameters that correspond to the vessel volumes, cap-
illary permeability, blood flow, and other aspects of
interest in the analysis. The preeminent models in this
respect were developed at the National Simulation Re-
source at the University of Washington (30 –32), and
these models have significantly advanced our under-
standing of the microcirculation in the heart. Such
models can be adapted to the analysis of MR perfusion
studies (16,28).
Compartmental Analysis
Lumped compartmental models can be reasonable ap-
proximations for describing the passage of a tracer
through myocardial tissue (33). For example, for Gd-
DTPA contrast agents, one can lump the vessels into a
vascular compartment, and the interstitial space into a
second compartment, with exchange of contrast agent
across the capillary barrier between these two spaces.
The use of lumped components in the model assumes
that the tracer mixes very rapidly within each compart-
ment (compared to the transfer of contrast material
through the vascular compartment and between com-
partments). This approximation neglects any spatial
tracer concentration gradients and the heterogeneity of
flows, both along vessels and in different vessels. Two-
compartment models have been applied successfully to
quantify blood flow in both positron emission tomogra-
phy (PET)-based (33) and MRI-based myocardial perfu-
sion studies (34). An example of the measured signal
time courses, and a fit of a two-compartment model are
shown in Fig. 7. The lumped two-compartment model is
mentioned here primarily as a simple example of a
tracer kinetic model. Generally, more sophisticated
Simulation Resource, are preferable because (in princi-
ple) they provide more accurate results, albeit at the
price of higher complexity (16).
If the exchange of tracer between the vascular space
and the tissue is assumed to be rapid, then the two
compartments can be lumped into one compartment,
resulting in the so-called Kety-Schmidt model. The
Kety-Schmidt model has been used to analyze the myo-
cardial tissue response to a slow infusion of Gd-DTPA
contrast agent (35). With a slow infusion of contrast
agent, the ratio of concentrations of Gd-DTPA in the
vascular and interstitial spaces is approximately con-
stant, i.e., the exchange of contrast agent across the
capillary barrier is rapid enough compared to the
changes in the arterial input. Cullen et al (36) used the
Kety-Schmidt model to calculate a perfusion reserve
index, and found that the index was inversely corre-
lated with the severity of the epicardial stenosis. The
flow index derived with the Kety-Schmidt model is a
product of the flow (F) and the efficiency of contrast
agent extraction (E) from the vascular into the intersti-
Analysis of Myocardial Perfusion MRI
Figure 7. The upper panel shows a schematic illustration of a
lumped two-compartment model, comprising a vascular space
compartment and an interstitial space compartment with
leakage and backflow of contrast agent between the two com-
partments controlled by the permeability surface area param-
eter (PS), and flow through the vascular space controlled by the
parameter F. Vv and Vi represent the respective volumes of the
compartments. The lower panel shows a measured SI curve for
an anterior myocardial sector and part of the arterial input
function (cin), measured in an ROI in the center of the LV. The
solid line is the solution of the two-compartment model that
best approximates the measured data in the least-squares
sense. A Marquard-Levenberg least-squares algorithm was
used for this example to optimize three of the model parame-
ters: the blood flow (F), the permeability surface area product
(PS), and the vascular space volume (Vv). The volume of the
interstitial space was fixed at 0.25 mL/g.
tial space, with E generally assumed constant between
rest and vasodilation (for lack of direct information
about E).
Model-Independent Analysis
Both the input function and the residue curve are mea-
sured for discrete time points t ⫽ (t1. . .tn), that we
assume are equally spaced. We adopt the convention
that the ith element qi of a vector qជ corresponds to its
value at the ith time point ti, e.g., q(t ⫽ ti) ⫽ qi. The
discretive form of Eq. [3] with cin(t) ⫽ i(t) is
冘 冘
i n
q共t i 兲 ⫽ q i ⬵ i共t i ⫺ ␶ j 兲 䡠 R共␶ j 兲 䡠 ⌬t ⫽
j⫽1 j⫽1
The variable ⌬t represents the sampling interval, and
the convolution operator A is a matrix calculated from
the arterial input i(t):
765
冤 冥
i1 0 ··· 0
i2 i1 ··· 0
A⫽ · · · · 䡠 ⌬t. (8)
· · · ·
· · · ·
in i n⫺1 ··· i1
Equation [7] represents a linear system of equations
that has to be solved in order for the impulse response
to determine the blood flow (37). The singular value
decomposition (SVD) provides a suitable framework for
determining whether a stable solution can be obtained
by straight inversion of Eq. [11] (38). The singular value
decomposition of a matrix A is defined by
SVD共A兲 ⫽ U 䡠 冘 䡠 VT, (9)
where U and V are orthogonal matrices (i.e., UUT ⫽ 1
and VVT ⫽ 1), ⌺ is a diagonal matrix with the singular
values ␴i decreasing as a function of the index i. VT is
the transpose of matrix V. We denote the columns vec-
tors of the orthogonal matrices U and V by u ជ i and u
ជ i,
respectively, and refer to them as singular vectors. The
singular vectors tend to have more sign changes in their
elements as the index i increases, i.e., as the singular
values ␴i become smaller. The formal solution of Eq. [7],
in terms of the singular vectors and the singular values
of A, is (38)
冘
s
ជ iT qជ
u
ជ ⫽
R vជ (10)
␴i i
i⫽1
An analysis of the singular values of the matrix A for
a typical arterial input shape shows (as in the example
in Fig. 8) that very small singular values (␴i), which
reflect noise in the measured data, render the expan-
sion in Eq. [10] unstable.
One can still calculate an approximate solution of Eq.
[7] from the singular value decomposition of A by filter-
ing out the contribution from the coefficients in Eq. [10]
that correspond to very small singular values. We used
an approach originally introduced by Tikhonov (39),
which consists of applying filter factors to the expan-
sion coefficients. In addition, we found it useful to rep-
resent the impulse response in terms of smooth B-
splines, which improves the condition of the input
matrix A, and reduces the degrees of freedom (37). A
spline-based representation of the impulse response
does not result in a significant bias toward underesti-
mating flows, particularly for myocardial blood flows
that reach 4 –5 mL/minute/g during hyperemia (37).
Such a model-independent approach for the quantifi-
cation of absolute myocardial blood flow requires min-
imal user input. We recently validated the model-inde-
pendent analysis of myocardial contrast enhancement
for both intravascular and extracellular contrast agents
(37,40).
A ij R j . (7) A related approach for determining the impulse re-
sponse was developed by Seethamraju et al (41), who
used the Steiglitz-McBride method (42) to determine
the coefficients of an autoregressive moving average
(ARMA) rational transfer function to approximate the
time-domain impulse response. Compared to the
766
Figure 8. SI curves for ROIs in the center of the LV cavity (solid line) and the anterior myocardial wall segment (dotted line) are
shown in the panel on the right. The panel on the left shows the divergence of the singular values (␴i) (dots) of the input matrix.
A series expansion for the impulse response (Eq. [13]) has expansion coefficients ˆ, shown in the graph as open circles. Their
divergence, as in this example, renders the calculation of the impulse response unstable unless the contributions from the
smallest singular values are filtered out.
Fermi-model– based analysis, model-independent de-
convolution provides an impulse response that is a
more accurate representation of the true impulse re-
sponse, albeit at the price of higher complexity in the
implementation of the algorithms. The model-indepen-
dent analysis works well for analyzing contrast en-
hancement with intravascular and extracellular con-
trast agents. For the extracellular contrast agents, the
Fermi model requires that the fit to the measured data
be limited to approximately the first pass, because the
leakage of contrast agent from the vascular space into
the interstitial space is not reproduced well by the
Fermi-function impulse response model. The model-
independent analysis overcomes this shortcoming of
the Fermi model.
Myocardial Perfusion Reserve (MPR)
The concept of flow reserve was developed (43) to deter-
mine the functional significance of a coronary artery
stenosis. The MPR is defined, in analogy to the coronary
flow reserve, as the ratio of hyperemic and basal myo-
cardial blood flow. We demonstrated that the MPR mea-
sured with the MR first-pass technique, and quantified
with a Fermi function model, correlated with the coro-
nary flow reserve in patients with microvascular dys-
function (2,26). In comparison to hyperemic blood flow,
blood flow measured for resting conditions is quite in-
sensitive to the lumen area reduction. Therefore, a re-
duction of the perfusion reserve is in most cases due to
a blunted hyperemic response (i.e., to changes in the
numerator of the perfusion reserve ratio); however, this
can not be established conclusively unless the absolute
blood flows for rest and hyperemia are also determined.
Due to the importance of flow reserves for the func-
tional evaluation of coronary artery lesions, many at-
Jerosch-Herold et al.
tempts have been made to derive a simplified method
for estimating the MPR from first-pass MR studies. For
this purpose, the ratio of the normalized up-slopes
measured for rest and vasodilation has been applied as
an estimate of the MPR. This method yielded good sen-
sitivities and specificities for detection of an abnormal
hyperemic response (3,4,18 –20). Nevertheless, the val-
ues for this perfusion index obtained with MRI in nor-
mal, healthy controls (3,4) fell considerably below per-
fusion reserves measured with other well-established
modalities, such as quantitative PET. Simulations are
consistent with this finding, as can be seen in Fig. 9.
Figure 10 illustrates this point with data acquired from
volunteers at our institution.
We have studied in more detail the relationship be-
tween the up-slope parameter and myocardial blood
flow (40). The change of SI in the LV, from the foot of the
input curve to the first-pass peak, can be approximated
as a constant rate input, i.e., the SI increases linearly as
a function of time: i(t) ⫽ a1 䡠 t. The up-slope of the
arterial input is denoted by a1. With this approxima-
tion, the convolution integral in Eq. [4] for the central
volume principle can be written as
冕
t
q共t兲 ⬇ R共␶兲 䡠 a 1 䡠 关t ⫺ ␶兴d␶. (11)
0
As a result, one obtains for the rate of change of the
residue function in response to a constant rate input
function:
dq共t兲
dt
⬇ a1 冕 0
t
R共␶兲 䡠 d␶, (12)
Analysis of Myocardial Perfusion MRI
Figure 9. The maximum up-slope and peak SI were used to
calculate a perfusion reserve ratio for simulated SI curves
corresponding to a range of blood flows up to 4 mL/minute/g.
The ratio is defined as the parameter value normalized by its
value at a flow of 1 mL/minute/g, the latter corresponding to
a typical myocardial blood flow for rest conditions. The SI
curves were simulated with a spatially-distributed, multiple-
path tracer kinetic model (MMID4, National Simulation Re-
source, University of Washington, Seattle). The same arterial
input function was used for all blood flow levels. The identity
relationship is shown as a dotted line. The perfusion reserve
estimate obtained from the up-slope parameter underesti-
mates the true perfusion reserve by 10 –30% over a range of
blood flows from 1 to 4 mL/minute/g. The perfusion reserve
estimate calculated from the peak SI gives an even worse
underestimate.
where R(t), the tissue impulse response, is a non-neg-
ative, monotonically decaying function of time. The
value of the integral in Eq. [12] therefore increases as a
function of t, meaning that the up-slope initially in-
creases with time during a constant rate input, and
only for t much larger than the mean transit time of the
impulse response does it reach a constant value in
response to a constant rate input. It can be shown that
Eq. [12] leads, under quite general assumptions, to the
following approximate proportionality relationship be-
tween the up-slope measured at time ts relative to the
foot of the curve, the slope of the arterial input (a1), and
myocardial blood flow F (40):
dq共t兲
⬀ a 1t s 䡠 F (13)
dt
We assumed that the contrast injection is rapid and
that the up-slope is measured at a time ts that is short
in comparison to the mean transit time. An MPR index
can be derived from the up-slope measurements, which
takes into account both the up-slope of the arterial
input and the time ts. We found that such a correction
to the slope ratio improves the agreement with the ratio
of myocardial blood flows measured during hyperemia
767
and rest (40), compared to an up-slope ratio that is only
normalized by the up-slope of the arterial input.
Collateral-Dependent Myocardium and Delayed
Arrival of Tracer
An interconnecting network of arterioles, which are re-
ferred to as (intracoronary) collaterals, can provide an
alternate path for blood flow to myocardium in the ter-
ritory of an occluded coronary artery. Recent studies in
patients have shown that resting blood flows in dys-
functional (but noninfarcted) collateral-dependent
myocardium are not significantly reduced compared to
remote segments (45). This finding has also been con-
firmed in animal studies of progressive, chronic isch-
emia induced by ameroid constrictor (46). Blood flow
through the collateral circulation is often insufficient to
prevent ischemia during exercise, and with maximal
vasodilation the increase in blood flow above its base-
line level is less than that in normal myocardium. In
collateral-dependent myocardium, the arrival of the
tracer may be delayed compared to normal myocar-
dium. This time delay may provide valuable information
for identifying collateral-dependent myocardium with-
out vasodilation, and for assessing to some degree the
functional capacitance of collateral vessels. In studies
Figure 10. MRI perfusion studies in 14 human volunteers
with the extracellular contrast agent Gd-DTPA (0.04 mmol/kg)
were acquired with a cardiac-gated, T1-weighted turbo-FLASH
sequence, with a saturation-recovery magnetization prepara-
tion (TR ⫽ 2.2 ms, TE ⫽ 1.1 ms, delay after saturation pulse
(TI) ⫽ 10 ms, flip angle (␣) ⫽ 18°, receiver bandwidth ⫽ 100
kHz, slice thickness ⫽ 8 mm). Hyperemia was induced over 3
minutes with i.v. adenosine (0.14 mg/minute/kg of body
weight i.v.) before acquisition of the perfusion images. The
solid line represents a least-squares, 2nd-order polynomial fit.
The perfusion reserve estimated from the up-slope parameter,
normalized by the up-slope of the arterial input, was compared
with the ratio of myocardial blood flows for hyperemia and
rest. A Bland-Altman analysis showed that the mean of the
relative difference between the perfusion reserve index and the
myocardial blood flow ratio averaged –22% (95% CI of –79% to
⫹38%).
768
Figure 11. SI curves for an anterior and a posterior myocar-
dial segment from a perfusion study of a patient with an oc-
cluded right coronary artery. The contrast enhancement in the
collateral-dependent posterior myocardial segment was signif-
icantly delayed with respect to the onset of contrast enhance-
ment in the anterior myocardial segment. The solid lines were
obtained by constrained deconvolution of the SI curves with an
arterial input function measured in the center of the LV. The
resulting blood flow estimates for the anterior and posterior
myocardial segments were 1.1 mL/minute/g and 0.95 mL/
minute/g, respectively. This example shows how collateral
vessels can preserve myocardial blood flow under rest condi-
tions.
of collateral development in a porcine model with amer-
oid constrictor, we have found that among the perfu-
sion parameters measured for resting conditions, the
delay time for arrival of an injected tracer in a collateral-
dependent segment (relative to the shortest delay ob-
served in the same short-axis slice) is a useful predictor
of a blunted hyperemic response, with a sensitivity and
specificity of 83% and 72%, respectively, and an opti-
mal threshold for the delay of td ⫽ 1.22 seconds (47).
Figure 12 shows an example of the remarkable delays
for contrast enhancement in collateral-dependent myo-
cardium—in this case, for a patient with an occluded
right coronary artery.
ADVANTAGES OF QUANTITATIVE ANALYSIS
It is crucial to quantify myocardial perfusion and the
MPR in patients with multiple-vessel coronary artery
disease. In such patients, the perfusion reserve is often
globally reduced, and a qualitative or semiquantitative
evaluation that detects only regional differences of per-
fusion reserve is inadequate for determining the sever-
ity of disease (43). Figure 11 shows how the perfusion
reserve calculated from absolute myocardial blood
flows declines with stenosis severity (44)
Al-Saadi et al (18) studied 35 patients with single-
and multivessel coronary artery disease before and 24
hours after intervention, and found that an MPR index
derived from the up-slope was significantly lower in
segments perfused by the stenotic artery than in the
control segments (1.07 ⫾ 0.24 vs. 2.18 ⫾ 0.35, P ⬍
0.001). The perfusion reserve index improved signifi-
Jerosch-Herold et al.
cantly after coronary intervention, but it did not reach
the same level as it did in the remote myocardial seg-
ments that served as controls. They concluded that the
quantitative analysis allowed them to observe an im-
provement of the MPR index after coronary interven-
tion, which was more pronounced after stenting than
after balloon percutaneous transluminal coronary an-
gioplasty.
Patients who have microcirculatory disease (syn-
drome X) and complain of chest pain, but also have a
normal coronary angiogram, have a globally reduced
flow reserve (28), which still leads to a relatively homo-
geneous contrast enhancement pattern compared to
patients with hemodynamically significant epicardial
lesions. Wilke et al (2) showed that both the MR perfu-
sion reserve and the coronary flow reserve were re-
duced, and they observed a good correlation between
invasive and noninvasive measurements (r ⫽ 0.80).
Therefore, in patients with chest pain and without an-
giographically visible epicardial lesions, the diagnosis
of microvascular disease can be made by quantitative
MR myocardial perfusion imaging. This point was rein-
forced by a more recent study (4).
We have developed a strong preference for largely
model-independent approaches to quantify myocardial
blood flow by the deconvolution analysis. In our expe-
rience, the deconvolution analysis is superior to a semi-
quantitative analysis for estimating the MPR. Further-
more, with appropriate image acquisition methods, and
for low contrast-agent dosages, it is feasible to estimate
absolute myocardial blood flow with the convolution
analysis. This has been validated in multiple studies
(8,37,40). With the up-slope parameter, one has to rely
on ratios of the parameter for rest and vasodilation to
assess the hyperemic response. Among the multiple
problems inherent to the use of ratios, we mention here
Figure 12. The MPR was determined in 44 patients with one-,
two-, and three-vessel disease as assessed by quantitative
coronary angiography (QCA). Lesion severity is indicated by %
luminal area reduction. Myocardial perfusion was quantified
with a Fermi-function model, and perfusion reserve values
were calculated as ratios of the perfusion estimates for hyper-
emia and rest, respectively. Each MPR value shown in the
graph represents the average MPR in the territory of the vessel
assessed by coronary angiography. In patients with a perfu-
sion territory supplied by a vessel without detectable lesion,
the respective perfusion reserve was also included in the above
graph in the “no lesion” category. Perfusion reserve values for
territories of vessels with bypass grafts are not included.
Analysis of Myocardial Perfusion MRI
that a ratio can introduce a bias in the results, and that
the calculation of a ratio increases the noise in the data.
The up-slope parameter is conceptually simpler than
the deconvolution analysis. The relationship of the up-
slope parameter to myocardial flow is not as clear-cut
as the relationship between the impulse response am-
plitude and blood flow (the latter was firmly established
by Zierler’s introduction of the central volume principle
in the 1960s (24,25)).
CONCLUSIONS
The analysis of myocardial perfusion presents the in-
vestigator with multiple choices in terms of accuracy,
efficiency, and the information that can be derived from
the analysis. Therefore, comparisons between MR myo-
cardial perfusion imaging and other tests for the detec-
tion and diagnosis of heart disease will continue to be
controversial, because the quality of the results hinges
on the approaches taken for the analysis of the perfu-
sion studies. In the near future, a wider availability of
cardiac perfusion analysis software, a growing consen-
sus in favor of quantitative analysis, and clinical trials
will help resolve these issues. Further improvements in
image acquisition, in terms of CNR and spatial resolu-
tion (possibly by the use of higher field strengths),
should considerably improve the accuracy of myocar-
dial perfusion analysis, and allow a more comprehen-
sive investigation of the myocardial microcirculation.
Even with the current state of the technology, MR myo-
cardial perfusion imaging looks quite favorable in com-
parison with other perfusion imaging modalities (48).
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