JACC: CARDIOVASCULAR IMAGING
VOL. 2, NO. 11, 2009
© 2009 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
ISSN 1936-878X/09/$36.00
DOI:10.1016/j.jcmg.2009.07.010
TECHNOLOGY ON THE VERGE OF TRANSLATION
Myocardial Blood Volume Is Associated With
Myocardial Oxygen Consumption
An Experimental Study With Cardiac Magnetic Resonance in a Canine Model
Kyle S. McCommis, BS,* Haosen Zhang, PHD,* Thomas A. Goldstein, MS,*
Bernd Misselwitz, PHD,‡ Dana R. Abendschein, PHD,† Robert J. Gropler, MD,*
Jie Zheng, PHD*
St. Louis, Missouri; and Berlin, Germany
Understanding the oxygen consumption of the left ventricular myocardium provides important insight
into the relationship between myocardial oxygen supply and demand. In other territories, cardiac magnetic resonance has been utilized to measure myocardial oxygen consumption with a blood level oxygen
dependent (BOLD) technique. The BOLD technology requires repetitive sampling of stationary tissues and
is frequently implemented in areas such as the brain. A limitation to utilizing BOLD cardiac magnetic
resonance techniques in the heart has been cardiac motion. In this study, we document a methodology for
acquiring BOLD images in the heart and demonstrate the utility of the technique for identifying associations between myocardial oxygen consumption and blood flow. (J Am Coll Cardiol Img 2009;2:1313–20)
© 2009 by the American College of Cardiology Foundation
Myocardial ischemia occurs when the supply of
oxygen is inadequate for the metabolic demand
of the myocardium. Measurements of myocardial perfusion (O2 supply) and myocardial oxygen consumption (MVO2) may provide accurate assessments of this balance in the heart.
Two important parameters for oxygen delivery
are myocardial blood flow (MBF) and myocardial blood volume (MBV). The addition of
MBV measurements increases the accuracy of
perfusion assessments because MBV has been
shown to be altered in situations of increased
MVO2 (1). The MBV is composed of vessels
ⱕ200 ␮m, of which 90% are capillaries. Because only ⬃50% of capillaries are functional at
rest, altering the amount of functional capillar-
ies can drastically change the tissue oxygenation levels.
Positron emission tomography (PET) is currently the only imaging modality capable of absolute quantification of regional myocardial perfusion and oxygen metabolism. The use of PET
permits the accurate quantification of MBF with
15
O-water and MVO2 with 11C-acetate. However, low spatial resolution, relatively long acquisition times, limited availability, relatively high
cost, and ionizing radiation discourage the widespread use of PET for these purposes. Furthermore, PET cannot measure MBV. Myocardial
contrast echocardiography (MCE) has the capability of measuring MBF and MBV but not
MVO2.
From the *Mallinckrodt Institute of Radiology and †Cardiovascular Division, Washington University School of Medicine,
St. Louis, Missouri; and ‡Bayer Schering Pharma AG, Berlin, Germany. This work was supported by NIH grant R01
HL74019-01. Dr. Misselwitz is an employee of Bayer Schering Pharma, which produces the Gadomer contrast agent used
in this study.
Manuscript received March 11, 2009; revised manuscript received June 16, 2009, accepted July 29, 2009.
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McCommis et al.
Regional Myocardial Perfusion and Oxygenation by CMR
Cardiac magnetic resonance (CMR) is a noninvasive imaging modality that provides excellent
image spatial resolution and soft-tissue contrast,
does not require ionizing radiation, and is widely
available. CMR can measure absolute MBF and
MBV via first-pass methods (2) and the oxygen
extraction fraction (OEF) by the use of the blood
oxygen level-dependent (BOLD) technique (3).
Fick’s law states that MVO2 ⬀ MBF ⫻ OEF;
therefore, CMR also can provide an estimation of
MVO2. The objective of this study was to apply
these comprehensive CMR techniques to evaluate
MBF, MBV, OEF, and MVO2 in a canine model
with control, moderate (75%), and severe (86% to
95%) coronary artery stenosis during dipyridamole
or dobutamine hyperemia. We hypotheABBREVIATIONS
size that direct measurements of these
AND ACRONYMS
parameters by CMR will facilitate a comprehensive ischemic assessment.
BOLD ⴝ blood oxygen
level-dependent
CMR ⴝ cardiac magnetic
resonance
LAD ⴝ left anterior descending
coronary artery
METHODS
Animal preparation. All animal procedures
were approved by the Animal Studies
LCX ⴝ left circumflex coronary
Committee at Washington University. A
artery
total of 21 (weight 24.7 ⫾ 3.0 kg) mongrel
LV ⴝ left ventricle
dogs were used, and they were divided into
MBF ⴝ myocardial blood flow
6 groups (Table 1). A thoracotomy was
MBV ⴝ myocardial blood
performed in the fourth intercostal space
volume
and the pericardium incised. The left anMCE ⴝ myocardial contrast
terior descending coronary artery (LAD)
echocardiography
was dissected free distal to the first diagMVO2 ⴝ myocardial oxygen
consumption
onal branch. The artery was instrumented
in a proximal-distal order with a Doppler
OEF ⴝ oxygen extraction
fraction
flow probe, a pneumatic occluder, and a
PET ⴝ positron emission
CMR-compatible stenosis clamp. The
tomography
procedure for setting the stenosis severity
ROI ⴝ region of interest
has been described previously. Serial 20-s
occlusions were performed to delineate the
hyperemic flow responses. After tightening the
stenosis clamp, another occlusion was performed to
assess the decrease in hyperemic flow. After attaining the desired level of stenosis defined by reduction
in hyperemic flow, the occluder was removed. The
dogs remained open-chest and were moved to the
magnetic resonance imaging suite. Control dogs
were omitted from thoracotomy surgery.
CMR was performed at rest and during
dipyridamole-induced vasodilation or dobutamineinduced hyperemia. Dipyridamole (Bedford Laboratories, Bedford, Ohio) was injected intravenously
at a dose of 0.14 mg/kg/min for 4 min. Dobutamine
(Hospira Inc., Lake Forest, Illinois) was started at 5
JACC: CARDIOVASCULAR IMAGING, VOL. 2, NO. 11, 2009
NOVEMBER 2009:1313–20
Table 1. Treatment Groups
Group # (n)
Stenosis, Area (%)
Pharmacologic Stressor
1 (4)
0
Dipyridamole
2 (4)
86
Dipyridamole
3 (3)
95
Dipyridamole
4 (4)
0
Dobutamine
5 (3)
75
Dobutamine
6 (3)
86–95
Dobutamine
␮g/kg/min and titrated at 5-␮g/kg/min increments
every 5 min until heart rate reached ⬎130 beats/
min (maximum of 30 ␮g/kg/min).
CMR imaging. Study timeline is shown in Figure 1.
Imaging was performed on a 1.5-T Sonata scanner
(Siemens Medical Solutions, Erlanger, Germany).
A 4-element phased array coil placed around the
chest was used for signal reception, and a body coil
was used as a transmitter. Scout imaging was
performed to obtain a short-axis image of the left
ventricle (LV) at the middle level of the papillary
muscles. During scans, respiratory motion was reduced by turning off ventilation to simulate breath
holding.
FIRST-PASS PERFUSION CMR PROTOCOL. Images
during the bolus injection of Gadomer (Bayer
Schering Pharma AG, Berlin, Germany), an intravascular contrast agent, were sequestered by a
saturation-prepared turbo fast low-angle shot sequence. The short-axis slice of the LV was acquired
during mid-diastole, triggered by the R-wave of the
electrocardiogram. A total of 60 to 80 dynamic
images were gathered, and images were collected at
every RR interval. Other imaging parameters included the following: time of repetition ⫽ 2.5 ms;
time of echo ⫽ 1.2 ms; time of inversion ⫽ 90 ms;
flip angle ⫽ 18°; field of view ⫽ 220 ⫻ 138 mm2;
matrix size ⫽ 128 ⫻ 80%; slice thickness ⫽ 8 mm;
and image acquisition time window per cardiac
cycle ⫽ 150 ms.
PROTOCOL FOR BOLD CMR. The BOLD effect was
detected by a multicontrast 2-dimensional segmented turbo spin-echo sequence. Double
inversion-recovery preparation yielded black-blood
images. The sequence was triggered by electrocardiogram with the turbo spin-echo train placed in
mid-diastole to minimize cardiac motion and
match the first-pass perfusion images. Parameters
included the following: field of view ⫽ 220 ⫻ 131
mm2; matrix size 256 ⫻ 156; slice thickness ⫽ 8
mm; inversion time ⫽ 350 to 500 ms, depending on
the RR interval; and data acquisition time ⫽ 24 ⫻
McCommis et al.
Regional Myocardial Perfusion and Oxygenation by CMR
JACC: CARDIOVASCULAR IMAGING, VOL. 2, NO. 11, 2009
NOVEMBER 2009:1313–20
RR, or 14.4 s for a typical 600-ms RR interval.
Three echo times, TE1 ⫽ 24, TE2 ⫽ 48, and
TE3 ⫽ 72, were used. At rest, this sequence was run
twice with 2 different echo spacings (␶ ⫽ 8 and ␶ ⫽
12) and at ␶ ⫽ 8 during hyperemia. The 2 T2 maps
with 2 echo spacings at rest were used to determine
model parameters for the calculation of OEF during hyperemia.
First-pass perfusion
images were analyzed with a JAVA program (Java
V5.0, Sun Microsystems, Santa Clara, California)
created in our lab. Images were denoised and
subjected to a validated perfusion quantification
algorithm (2). This algorithm created both MBF
and MBV maps, on which regions of interest
(ROIs) could be drawn. We determined MBV by
MBF divided by mean transit time. The mean
transit time was determined by the area under the
impulse curve, and images before the second contrast pass were removed. Details of this estimation
were shown in a previous report.
We analyzed BOLD T2-weighted images with a
MATLAB graphics program (The MathWorks,
Natick, Massachusetts). Pixel-by-pixel maps of the
myocardial T2 decay constants were calculated from
the signal intensities, and then OEF maps during
hyperemia were determined with our previously
described model (3), on which ROIs similar to the
first-pass perfusion map ROIs were drawn. A resting OEF of 0.6 was assumed, which is based on
arterial and coronary sinus blood sampling measurements in control dogs at rest (R2 ⫽ 0.90), as
well as PET measurements in dogs with moderate
stenosis (R2 ⫽ 0.75). Sample perfusion and OEF
maps are shown in Figure 2.
IMAGE POST-PROCESSING.
CALCULATION OF MVO2. Once MBF and OEF
were determined, MVO2 was calculated using
Fick’s law:
MVO2 ⫽ [O2]a ⫻ OEF ⫻ MBF
(1)
The constant [O2]a is defined as the total oxygen
content of arterial blood, and a value of 7.99
␮mol/ml was used.
Data analysis. The MBF, MBV, OEF, and MVO2
data are presented as mean ⫾ SD. Percentage
change (from rest to hyperemia) was determined. A
paired and unpaired t test was used to compare
between rest and pharmacologic stress and between
stenosed and control dogs, respectively. Linear correlations between these parameters were expressed
Anesthesia
BOLD First-pass
Imaging Perfusion
10-20
Stenosis Created
2-3
BOLD First-pass
Imaging Perfusion
50
10-20
2-3
KC1
Euthanasia
Time (min)
Pharmacologic
Stressor Started
Figure 1. Imaging Study Protocol
The blood oxygen level-dependent (BOLD) method was used to evaluate
the myocardial oxygen extraction fraction, and first-pass perfusion was used
to evaluate both myocardial blood flow and volume. The BOLD and firstpass perfusion scans were performed at rest and during either intravenous
dipyridamole or dobutamine hyperemia. The numbers below the line represent the approximate time in minutes between events.
as the coefficients of determination. Comparison
tests between 2 R2 values were performed by use of
a Z test. A p value ⬍0.05 signified significant
differences.
RESULTS
Hemodynamics. Table 2 displays the hemodynamic
changes. As expected, dipyridamole caused only
slight changes in rate-pressure product (p ⫽ NS),
whereas dobutamine produced significant increases
in rate-pressure product (p ⬍ 0.05).
Absolute MBF and MBV values. The absolute MBF
and MBV values, as well as percent change values
for all groups, are displayed in Tables 3 and 4,
respectively. During dipyridamole, control dogs
achieved 2- to 3-fold increases in MBF. Stenosis
attenuated these MBF reserves in the LAD region
and in the remote left circumflex coronary artery
(LCX) region with severe 95% LAD stenosis. The
dobutamine groups had similar trends in MBF. The
trend for attenuation of increased MBF in the remote
LCX region was not statistically significant but is in
agreement with other reports.
In control dogs, dipyridamole and dobutamine
induced moderate 30% and ⬎50% changes in
MBV, respectively. Stenosis ⬎86% dramatically
attenuated the MBV increases in the LAD region
during either dipyridamole vasodilation or dobutamine hyperemia. Such attenuation also was observed in the remote LCX region, especially with
dobutamine injection. However, for 75% area stenosis during dobutamine, the attenuation of MBV
was much less, although significant changes were
still observed relative to the resting values.
Values for OEF and MVO2. The hyperemic OEF and
MVO2 values, as well as the percent change values,
are presented in Tables 5 and 6, respectively. As
expected, in control dogs dipyridamole caused large
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McCommis et al.
Regional Myocardial Perfusion and Oxygenation by CMR
JACC: CARDIOVASCULAR IMAGING, VOL. 2, NO. 11, 2009
NOVEMBER 2009:1313–20
both MVO2 and MBF, which in control dogs
produced no significant change in OEF. Only small
OEF changes were observed in the stenotic and
remote regions.
In control dogs, dipyridamole caused moderate
30% to 70% increases in MVO2 (4). The LAD
stenosis attenuated the MVO2 increases in the
LAD- and LCX-perfused regions. Dobutamine
resulted in significantly larger increases in MVO2 in
control dogs. However, even 75% stenoses significantly reduced the change in MVO2 in both the
LAD- and LCX-perfused regions.
Relationship between myocardial perfusion and oxygen utilization. Correlations between MVO2 reserve
Figure 2. Representative Short-Axis Maps From a Dog With a
96% LAD Stenosis During Dipyridamole
The myocardial blood flow map (A) and myocardial blood volume map (B), derived from the first-pass perfusion images,
clearly show an anterior perfusion defect. The extraction fraction
map (C), derived from the blood oxygen level-dependent
T2-weighted images, shows greater extraction fraction in the
stenotic anterior region as the result of the decreased oxygen
supply. The stenotic LAD region is marked with a yellow region
of interest. The myocardial blood flow scale units are ml/min/g
(A); myocardial blood volume scale units are ml/g (B). LAD ⫽
left anterior descending; LV ⫽ left ventricle.
decreases in OEF. These decreases also were observed in the remote normal LCX regions of the
dogs with coronary stenosis. Dobutamine increased
versus MBF or MBV reserve for dogs with and
without coronary artery stenosis in the LAD and/or
LCX (in control dogs) subtended regions are plotted in Figure 3. In control dogs, MBV reserve
shows mild-to-moderate correlation with MVO2
reserve with dobutamine stress but not with dipyridamole vasodilation (Fig. 3A). In dogs with stenosis, MBF reserve appears to correlate well with
MVO2 reserve, and similar correlations were observed between dipyridamole and dobutamine hyperemia. With stenosis, MBV reserve again appears
much less correlated with MVO2 during dipyridamole vasodilation. However, with the larger increases in MVO2 with dobutamine, MBV reserve
appears to be strongly correlated with MVO2 reserve, although the p values for the correlation
coefficients were not statistically different as the
result of limited data points. It is noted that during
dobutamine, the slope of MBV reserve versus
MVO2 reserve is also greater than MBF reserve
versus MVO2 reserve, indicating a better association with MBV reserve. From this point of view,
MBV may be a significant source of O2 supply
when MBF supply becomes exhausted with increased O2 demand in settings of coronary artery
stenosis.
DISCUSSION
The purpose of this study was to apply our noninvasive CMR techniques to directly assess regional
microcirculatory changes that occur during dipyridamole and dobutamine stress. To our knowledge,
this is the first study to show that regional MBF,
MBV, OEF, and MVO2 can be assessed noninvasively in a single imaging session. The role of MBV
during increased O2 demand is also confirmed in
this study.
McCommis et al.
Regional Myocardial Perfusion and Oxygenation by CMR
JACC: CARDIOVASCULAR IMAGING, VOL. 2, NO. 11, 2009
NOVEMBER 2009:1313–20
Table 2. Hemodynamics for Control and Stenosed Dog Groups
Control Dogs
Stenosed Dogs
HR
SBP
RPP
HR
SBP
RPP
Rest
93.5 ⫾ 6.1
78.7 ⫾ 15.5
7,356.5 ⫾ 1,528.7
101.9 ⫾ 16.3
88.7 ⫾ 12.3
8,784.9 ⫾ 2,217.4
DIP
91.7 ⫾ 11.9
77.8 ⫾ 22.0
7,181.6 ⫾ 2,722.7
101.5 ⫾ 18.0
82.8 ⫾ 13.4
8,350.8 ⫾ 2,872.3
DOB
113.8 ⫾ 18.9*
111.0 ⫾ 28.8*
13,006.1 ⫾ 5,343.4*
138.7 ⫾ 18.3*
121.6 ⫾ 27.4*
1,7033.0 ⫾ 3,873.0*†
∆ DIP (%)
⫺2.4 ⫾ 12.8
⫺6.7 ⫾ 12.1
⫺9.4 ⫾ 18.5
2.4 ⫾ 12.7
∆ DOB (%)
21.1 ⫾ 23.4
39.1 ⫾ 25.3
72.7 ⫾ 62.0
46.8 ⫾ 37.7†
⫺9.3 ⫾ 3.3
39.5 ⫾ 33.1
⫺16.4 ⫾ 8.7
114.8 ⫾ 83.5†
Values presented as mean ⫾ SD. *p ⬍ 0.05 for stress versus rest. †p ⬍ 0.05 for stenosed versus control dogs.
DIP ⫽ dipyridamole; DOB ⫽ dobutamine; HR ⫽ heart rate; RPP ⫽ rate pressure product; SBP ⫽ systolic blood pressure; ∆ ⫽ percent change.
Dogs during dipyridamole. By using blood sampling
techniques in control dogs, Hoffman et al. (4)
observed MVO2 increases of 70% with adenosine
vasodilation, which is comparable with our 30% to
70% increases in MVO2 using dipyridamole. In
comparison with the control groups, resting MBF
of LAD regions in the 86% and 95% stenosis
groups significantly reduced 38% (p ⬍ 0.01) and
42% (p ⫽ 0.02), respectively. However, after normalizing the resting MBF by rate-pressure product,
there is no statistical difference between control and
either stenosis groups for the resting MBF (MBF/
rate-pressure product ⫻ 104: 0.46 ⫾ 0.43 ml/g/min
in control vs. 0.78 ⫾ 0.09 ml/g/min in the 86%
stenosis group or vs. 0.61 ⫾ 0.24 ml/g/min in the
95% stenosis group). Similar decreases in MBF
reserve have been observed in dogs and clinically
with MCE and PET. Although they showed
⬃130% increases in MBF in normal regions of
animals with stenosis (we showed 140% to 200%),
they also observed only ⬃24% increases in MBF in
the zone distal to the stenosis (we showed 12% to
Table 3. Myocardial Blood Flow (ml/min/g)
Table 4. Myocardial Blood Volume (ml/100 g)
Group
Stenosis
LAD
LCX
Group
1
Rest
1.0 ⫾ 0.2
1.0 ⫾ 0.2
DIP
2.9 ⫾ 0.8*
3.1 ⫾ 0.6*
198.9 ⫾ 29.7
231.2 ⫾ 53.1
% change
2
DIP
% change
1.1 ⫾ 0.3
0.8 ⫾ 0.1†
3.1 ⫾ 0.6*
29.1 ⫾ 4.1†
200.8 ⫾ 75.3
Rest
0.6 ⫾ 0.1†
1.5 ⫾ 0.5
0.6 ⫾ 0.2†
3.6 ⫾ 1.1*
2
LCX
11.9 ⫾ 6.9†
139.7 ⫾ 50.8‡
Rest
1.1 ⫾ 0.3
1.0 ⫾ 0.3
DOB
3.0 ⫾ 0.6*
3.0 ⫾ 0.6*
191.6 ⫾ 69.0
204.4 ⫾ 75.3
Rest
0.8 ⫾ 0.0
1.2 ⫾ 0.3
DOB
1.2 ⫾ 0.1†
4.3 ⫾ 0.8*
5
143.9 ⫾ 8.4
0.8 ⫾ 0.1
1.3 ⫾ 0.1
DOB
1.1 ⫾ 0.2†
2.8 ⫾ 1.0*
% change
40.0 ⫾ 10.5†
130.5 ⫾ 65.5
Myocardial blood flow values presented as mean ⫾ SD in ml/g/min; *p ⬍ 0.05
for stress versus rest, †p ⬍ 0.05 for control versus stenosis, ‡p ⬍ 0.05 for
dipyridamole groups 2 versus 3, or for dobutamine groups 5 versus 6.
LAD ⫽ left anterior descending perfused region; LCX ⫽ left circumflex
perfused region; other abbreviations as in Table 2.
7.8 ⫾ 1.2*
7.6 ⫾ 0.9*
33.3 ⫾ 20.6
40.1 ⫾ 28.2
86%
4.0 ⫾ 1.1†
6.0 ⫾ 1.6†
DIP
4.7 ⫾ 1.3†
9.0 ⫾ 0.6*
21.0 ⫾ 21.1
36.7 ⫾ 33.1
95%
Rest
3.7 ⫾ 0.4†
6.0 ⫾ 1.5
DIP
4.7 ⫾ 1.6†
9.0 ⫾ 1.5*
22.8 ⫾ 28.8
53.0 ⫾ 24.5
Rest
5.3 ⫾ 0.3
4.7 ⫾ 0.3
DOB
7.9 ⫾ 1.2*
7.7 ⫾ 1.4*
50.8 ⫾ 29.9
60.4 ⫾ 21.0
Control
75%
Rest
4.3 ⫾ 0.7
7.3 ⫾ 1.3†
DOB
7.0 ⫾ 2.4
10.6 ⫾ 0.7*†
36.0 ⫾ 9.0
48.5 ⫾ 19.2
% change
6
5.6 ⫾ 1.0
Rest
% change
86%–95%
Rest
5.9 ⫾ 0.9
DIP
% change
4
75%
55.0 ⫾ 11.7†
Rest
% change
3
Control
% change
6
0.6 ⫾ 0.1†
DIP
% change
5
LAD
Control
% change
95%
% change
4
1
86%
Rest
3
Stenosis
Control
86%–95%
Rest
3.2 ⫾ 0.6†
DOB
3.9 ⫾ 0.4†
7.4 ⫾ 0.8‡
25.9 ⫾ 13.1†‡
20.5 ⫾ 10.4†‡
% change
6.2 ⫾ 0.9†
Myocardial blood volume values presented as mean ⫾ SD in ml/100 g; *p ⬍
0.05 for stress versus rest, †p ⬍ 0.05 for control versus stenosis, ‡p ⬍ 0.05 for
dipyridamole groups 2 versus 3 or for dobutamine groups 5 versus 6.
Abbreviations as in Tables 2 and 3.
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Regional Myocardial Perfusion and Oxygenation by CMR
JACC: CARDIOVASCULAR IMAGING, VOL. 2, NO. 11, 2009
NOVEMBER 2009:1313–20
Table 5. Oxygen Extraction Fraction
Group
1
Stenosis
Rest
0.60 ⫾ 0.00
0.60 ⫾ 0.00
0.27 ⫾ 0.17*
0.32 ⫾ 0.12*
Rest
0.60 ⫾ 0.00
0.60 ⫾ 0.00
0.54 ⫾ 0.03†
0.31 ⫾ 0.09*
⫺49.1 ⫾ 14.8
Rest
0.60 ⫾ 0.00
0.60 ⫾ 0.00
DIP
0.60 ⫾ 0.02†
0.31 ⫾ 0.10*
0.5 ⫾ 8.6†
⫺48.6 ⫾ 16.3
Rest
0.60 ⫾ 0.00
0.60 ⫾ 0.00
DOB
0.54 ⫾ 0.12
0.58 ⫾ 0.11
⫺10.2 ⫾ 19.7
⫺2.6 ⫾ 18.2
Control
75%
Rest
0.60 ⫾ 0.00
0.60 ⫾ 0.00
DOB
0.62 ⫾ 0.04
0.64 ⫾ 0.06
3.0 ⫾ 7.5
7.3 ⫾ 10.6
Rest
0.60 ⫾ 0.00
0.60 ⫾ 0.00
DOB
0.57 ⫾ 0.04
% change
6
⫺12.9 ⫾ 5.4†
95%
% change
5
⫺46.9 ⫾ 19.7
DIP
% change
4
⫺54.5 ⫾ 28.7
86%
% change
3
LCX
DIP
% change
2
LAD
Control
86%–95%
% change
⫺5.6 ⫾ 6.8
0.49 ⫾ 0.06*‡
⫺17.6 ⫾ 10.4‡
Oxygen extraction fraction values presented as mean ⫾ SD; *p ⬍ 0.05 for
stress versus rest, †p ⬍ 0.05 for control versus stenosis, ‡p ⬍ 0.05 for
dipyridamole groups 2 versus 3, or for dobutamine groups 5 versus 6.
Abbreviations as in Tables 2 and 4.
29%). The changes in MVO2 in the LAD stenotic
region during dipyridamole vasodilation were observed at a similar level for both 86% and 95%
severe stenosis.
It has been suspected that a primary method of
reducing MBV is a reduction in perfusion bed size.
These data support the notion that MBV plays a
mediating role in the match/mismatch of MBF and
MVO2 (1). Our MBV findings during dipyridamole conform to other reports (1) in that no significant relationship exists between MBV and small
changes in MVO2 caused by chronotropic stimulation alone.
Dogs during dobutamine. In control dogs, we observed 157% to 194% increases in MVO2 with
dobutamine. This large O2 demand was accounted
for by 192% to 204% increases in MBF and 51% to
60% increases in MBV. These findings are similar
to Le et al. (1), who found ⬃200% increases in
MBF and 90% to 150% increases in MVO2 in
normal dogs with varying dobutamine doses. With
75% area stenosis, the region distal to the stenosis
had dramatic attenuation of MVO2 increase. This
finding was associated with a similar rate of reduction of MBF reserve in the stenotic LAD region,
and OEF remained similar to rest. The MBV
increase was slightly attenuated in the 75% area
stenosis regions than in control dogs. With further
increase in stenosis severity, both MBF and MBV
reserve were attenuated, and OEF again remained
the same as at rest, resulting in less MVO2 increase.
Similar trends were observed in the remote LCX
region.
A recent study (5) in which the authors used
radiolabeled microspheres in dogs showed the remote regions of dogs with coronary stenosis had a
216% MBF increase, whereas the region distal to
the stenosis showed only a 20% increase in MBF.
By using blood sampling techniques, they also
showed large increases in MVO2 with dobutamine
before stenosis (120%) and significantly attenuated
MVO2 increases with dobutamine after stenosis
(20%).
The MBV has a close relationship with MVO2
when inotropic stimulation (as with dobutamine)
induces relatively large changes in MVO2. This can
Table 6. Myocardial Oxygen Consumption Rate
Group
1
2
3
4
5
6
Stenosis
LAD
LCX
Control
Rest
4.82 ⫾ 0.90
DIP
6.75 ⫾ 4.46*
4.75 ⫾ 0.99
8.35 ⫾ 3.64*
% change
33.5 ⫾ 75.9
73.9 ⫾ 55.8
86%
Rest
2.97 ⫾ 0.28†
5.38 ⫾ 1.57
DIP
3.32 ⫾ 0.29*
7.83 ⫾ 2.43*
% change
12.3 ⫾ 6.3
45.9 ⫾ 15.1
95%
Rest
2.78 ⫾ 0.59†
7.55 ⫾ 2.35
DIP
3.13 ⫾ 1.02*
8.84 ⫾ 2.51
% change
11.9 ⫾ 8.6
17.9 ⫾ 13.4‡
Control
Rest
5.18 ⫾ 1.14
4.97 ⫾ 1.19
DOB
13.41 ⫾ 4.77*
14.25 ⫾ 3.82*
% change
156.9 ⫾ 58.3
193.9 ⫾ 72.2
75%
Rest
3.75 ⫾ 0.19
DOB
5.99 ⫾ 0.69*†
22.81 ⫾ 5.59*
8.61 ⫾ 1.26†
% change
59.3 ⫾ 11.4†
162.3 ⫾ 33.5
86%–95%
Rest
3.98 ⫾ 0.67
6.21 ⫾ 0.57‡
DOB
5.23 ⫾ 0.73†
11.70 ⫾ 4.81*
% change
31.8 ⫾ 5.3†‡
91.5 ⫾ 51.2†
Myocardial oxygen consumption values presented as mean ⫾ SD in
ml/kg/min; *p ⬍ 0.05 for stress versus rest, †p ⬍ 0.05 for control versus
stenosis, ‡p ⬍ 0.05 for dipyridamole groups 2 versus 3, or for dobutamine
groups 5 versus 6.
Abbreviations as in Tables 2 and 4.
McCommis et al.
Regional Myocardial Perfusion and Oxygenation by CMR
JACC: CARDIOVASCULAR IMAGING, VOL. 2, NO. 11, 2009
NOVEMBER 2009:1313–20
MBV Reserve
A4
DIP
y = -0.09x + 1.51
R2 = 0.06
DOB y = 0.23x + 0.92
R2 = 0.36
3
2
1
0
1
2
3
MVO2 Reserve
B
4
DIP
MBF Reserve
0
3
DOB y = 0.55x + 0.68
R2 = 0.53
4
y = 1.09x - 0.00
R2 = 0.66
2
1
0
1
0
MBV Reserve
C4
DIP
2
3
MVO2 Reserve
4
y = 0.84x + 0.28
R2 = 0.26
DOB y = 1.56x - 0.84
R2 = 0.79
3
2
1
0
0
1
2
3
MVO2 Reserve
4
Figure 3. Regression Analysis to Discern Relationships Among
MBF, MBV, and MVO2 Reserve During Dipyridamole or
Dobutamine
(A) Control dogs show only mild and moderate correlation
between MBV reserve and MVO2 reserve during dipyridamole
(DIP) (pink circles) and dobutamine (DOB) (green circles),
respectively. (B) In stenotic regions, MBF reserve is slightly more
correlated with MVO2 reserve during DIP (pink circles). (C) However, MBV reserve is more correlated with MVO2 reserve during
DOB (green circles). This finding supports the theory that MBV
is required during inotropic stimulation when MVO2 is more significantly increased. MBF ⫽ myocardial blood flow; MBV ⫽ myocardial blood volume; MVO2 ⫽ myocardial oxygen consumption.
be observed from Figure 3; when MVO2 was only
moderately increased with dipyridamole, MBF reserve had a closer relationship to MVO2 reserve
than MBV reserve. When MVO2 was more significantly altered with dobutamine, MBV reserve was
more closely associated with MVO2 reserve. These
results are in agreement with MCE findings showing that minor increases in MVO2 can be met by
increases in MBF alone but major MVO2 increases
require increases in MBV as well.
Study limitations. There are several factors that affect
these quantification methods for OEF and MVO2.
First, there is no CMR quantification method for
absolute OEF at rest. Thus, we must assume a rest
OEF of 0.6 and determine the hyperemic OEF based
on change in T2 during hyperemia. Although this may
induce systematic errors, the hyperemic OEF was
closely correlated with other gold standards, either by
blood sampling (3) or by PET. Second, spatial resolution and signal-to-noise ratio are limited to differentiate endomyocardium and epimyocardium. These
transmural gradients in myocardial perfusion and oxygenation are important for the diagnosis of myocardial ischemia. Although MBF and MBV maps could
be analyzed for this purpose, the major limitation lies
in the OEF map that is created by a T2 map using a
3-echo fitting procedure. Such a low number of
echoes created “mapping noise” that caused a large
spatial variation in T2. Other T2-weighted methods or
more echo numbers may be needed to reduce the
noise. Finally, LV wall motion may hamper the
accuracy of myocardial T2 measurement. Although
images are acquired at mid-diastole, i.e., the relatively
motionless period within one cardiac cycle, we have
observed LV motion among images with different
echo times. This cardiac motion often occurs with
increased heart rates during dobutamine hyperemia.
Because we used double inversion recovery technique
to minimize blood flow signal in the LV, this cardiac
motion also reduced the efficiency of the blood flow
signal suppression. Therefore, combined adverse effects of this motion may attenuate or lengthen the
echo train of the T2 decay curve. Given the complexity of these motion effects, no simulation was
yet performed to estimate the error from these
effects. However, on the basis of our experience, the
possible error could be up to 5% of the myocardial
T2, which is close to the precision we observed in
normal dogs (3). This would lead to an error of 14%
in the estimation of OEF. Efforts to reduce this
cardiac motion are one of our laboratory’s ongoing
projects.
1319
1320
McCommis et al.
Regional Myocardial Perfusion and Oxygenation by CMR
JACC: CARDIOVASCULAR IMAGING, VOL. 2, NO. 11, 2009
NOVEMBER 2009:1313–20
CONCLUSIONS
The combination of the CMR methods used in this
study facilitates the comprehensive evaluation of microcirculatory pathophysiology caused by coronary
stenosis. Notably, MBV appears to correlate with
significantly increased MVO2 in both normal and
ischemic myocardial regions. Because even a moderate
stenosis during stress effects not only O2 delivery
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Key Words: cardiac magnetic
resonance y myocardial blood
flow y myocardial blood volume
y myocardial oxygen
consumption y blood oxygen
level dependent.