(Circulation. 2000;101:1379.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Noninvasive Detection of Myocardial Ischemia From Perfusion Reserve Based on Cardiovascular Magnetic Resonance
From the Department of Internal Medicine/Cardiology, German Heart Institute Berlin and Charité, Campus Virchow, Humboldt University, Berlin, Germany.
Correspondence to Eike Nagel, MD, Internal Medicine/Cardiology, German Heart Institute and Charité, Campus Virchow, Humboldt University, Augustenburger Platz 1, D-13353 Berlin, Germany. E-mail eike.nagel{at}dhzb.de
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Abstract |
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Background—Myocardial perfusion reserve can be noninvasively assessed with cardiovascular MR. In this study, the diagnostic accuracy of this technique for the detection of significant coronary artery stenosis was evaluated.
Methods and Results—In 15 patients with single-vessel
coronary artery disease and 5 patients without significant
coronary artery disease, the signal intensity–time curves of
the first pass of a gadolinium-DTPA bolus injected through a central
vein catheter were evaluated before and after
dipyridamole infusion to validate the technique. A
linear fit was used to determine the upslope, and a cutoff value for
the differentiation between the myocardium supplied by
stenotic and nonstenotic coronary arteries was
defined. The diagnostic accuracy was then examined
prospectively in 34 patients with coronary artery disease and
was compared with coronary angiography. A significant
difference in myocardial perfusion reserve between ischemic and
normal myocardial segments (1.08±0.23 and 2.33±0.41;
P<0.001) was found that resulted in a cutoff value of
1.5 (mean minus 2 SD of normal segments). In the prospective
analysis, sensitivity, specificity, and diagnostic
accuracy for the detection of coronary artery stenosis
(
75%) were 90%, 83%, and 87%, respectively. Interobserver and
intraobserver variabilities for the linear fit were low
(r=0.96 and 0.99).
Conclusions—MR first-pass perfusion measurements yielded a high diagnostic accuracy for the detection of coronary artery disease. Myocardial perfusion reserve can be easily and reproducibly determined by a linear fit of the upslope of the signal intensity–time curves.
Key Words: magnetic resonance imaging • perfusion • coronary disease
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Introduction |
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TopAbstractIntroductionResultsDiscussionMethodsReferences |
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In principle, the reduction of myocardial perfusion is a sensitive indicator for myocardial ischemia because myocardial blood flow is directly correlated to myocardial oxygen supply. Such measurements are superior to coronary angiography for the detection of myocardial ischemia because the functional relevance rather than the morphological appearance of a stenosis is assessed. Furthermore, the analysis of perfusion may permit the estimation of collateralization. Clinical routine measurements of myocardial perfusion are performed with single-photon emission computed tomography (SPECT) or with positron emission tomography (PET). Sensitivity and specificity for the detection of significant coronary artery disease with SPECT or PET range from 83% to 95% and 53% to 95%.1 2 3 4 However, these techniques have a rather low spatial resolution and are not suitable for the detection of subendocardial perfusion defects, which by themselves are extremely sensitive to the occurrence of myocardial ischemia.5 In addition, the requirement of radioactive markers prohibits the use of these techniques for follow-up examinations, and SPECT imaging is limited by attenuation artifacts.1 PET has a higher sensitivity and specificity than SPECT1 4 but is burdened by its limited availability.
MR tomography allows an analysis of myocardial perfusion by the use of the first pass of a T1-shortening contrast agent bolus.6 7 8 9 10 11 12 13 14 15 16 17 18 Several studies have shown in principle that an analysis of myocardial perfusion with MR is possible and may even permit a quantitative assessment of myocardial blood flow.13 16 The concept of myocardial perfusion measurements from the first pass of a contrast agent has been extensively validated in experimental animals.7 8 13 14 17 Under optimal conditions, such as injection of the contrast agent into the left atrium or the use of an intravascular contrast agent, a close correlation to microsphere or coronary flow measurements was found.13 14 In healthy control subjects and in small numbers of patients, the concept also has been shown to be useful.9 10 11 12 15 16 18 To reduce the error introduced by diffusion of the extracellular tracer used in humans and to improve sensitivity, the determination of perfusion reserve was suggested and has been shown to be beneficial.12 However, to date, no easy and reproducible way that enables a clear identification of ischemic myocardial segments has been reported.
Thus, the aim of this study was to define a threshold value for ischemic regions by myocardial perfusion reserve. This was measured by cardiovascular MR to differentiate the myocardium supplied by a stenotic coronary artery from the myocardium supplied by a nonstenotic coronary artery. Also, we aimed to determine prospectively the diagnostic accuracy of this cutoff value for the detection of significant coronary artery stenosis in patients with suspected coronary artery disease.
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Results |
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Dipyridamole stress MR perfusion imaging was successfully performed in all patients of group A and in 34 of the 40 (85%) patients of group B (see Methods). In group B, 3 (7.5%) patients were excluded because of claustrophobia. In 3 (7.5%) patients, ECG triggering was insufficient because of frequent premature ventricular complexes (n=2) or atrial fibrillation, which developed at the beginning of the MR examination (n=1). Neither the dipyridamole infusion nor the placement of the central venous catheter caused any serious side effects requiring active treatment; however, the usual side effects of dipyridamole were observed. In all patients, it was possible to perform the second MR perfusion measurement during dipyridamole infusion. In 19 (3%) of the 648 signal intensity (SI) curves of all evaluated myocardial segments, curve fitting was not possible because of artifacts or noise.
Validation
Interobserver and intraobserver variabilities for the
determination of the upslope yielded excellent correlations
(r=0.96 and 0.99, respectively). Relative differences were
8.3±9.9% and 3.9±4.7%, respectively (Figure 1
).
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In group A, no significant difference between myocardial segments
supplied by stenotic coronary arteries (median area
stenosis 94%) and contralateral myocardial segments supplied
by normal coronary arteries was found at rest (1.6±0.7 vs
1.6±0.8). After dipyridamole infusion there was a
significant difference between the ischemic and the
nonischemic myocardial segments (2.1±0.9 vs 2.9±1.0;
P<0.05) (Figure 2). However,
because of an overlap of the 2 groups at rest and during
dipyridamole stimulation, no cutoff could be defined
from these values.
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) at rest and after
vasodilatation with dipyridamole (stress) in group A
represented as single values and mean±1 SD. Differences
between ischemic and control segments at rest were not
significant.
Myocardial perfusion reserve after dipyridamole
infusion resulted in highly significant differences between myocardial
segments supplied by stenotic coronary arteries
(1.08±0.23) and nonstenotic coronary arteries
(2.34±0.41; P<0.001) (Figure 3). A cutoff value of 
1.5 was
defined.
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In group B, 60 coronary artery stenoses were found by angiography (left anterior descending [LAD] 20, left circumflex [LCX] 21, right coronary artery [RCA] 19, median area stenosis 89%). Thirteen (38%) patients had single-vessel disease and 16 (47%) had double-vessel disease. In 5 (15%) patients, triple-vessel disease was found despite previously expected double-vessel disease.
In this group, myocardial perfusion reserve was 1.16±0.29 in the
ischemic segments and 2.17±0.62 in the nonischemic
segments (P<0.001). Fifty-four of the 60 segments supplied
by stenotic coronary arteries and 35 of the 42 segments
supplied by nonstenotic coronary arteries were
correctly classified by the use of the defined myocardial perfusion
reserve cutoff value of 1.5, resulting in a sensitivity of 90%, a
specificity of 83%, and a diagnostic accuracy of 87%
(Table 1).
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Discussion |
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TopAbstractIntroductionResultsDiscussionMethodsReferences |
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MR perfusion imaging can be used to detect coronary artery stenosis with high diagnostic accuracy. In this study, a sensitivity of 90% and a specificity of 83% for the detection of significant coronary artery stenosis was reached in 34 patients by the use of a previously defined threshold for ischemic myocardial regions. A linear fit of the upslope of the first pass of a gadolinium-DTPA bolus before and after dipyridamole infusion enabled an easy and reproducible determination of the myocardial perfusion reserve.
In this study, a new and easy approach for the determination of
myocardial perfusion reserve was used. In contrast to previous studies,
which applied a 
-variate fit,13 16 18 19 a linear fit
of the upslope of the SI-time curves of the first-pass bolus of a
contrast bolus injection was performed. The concept of a -variate
fit was used for the quantification of myocardial perfusion in
PET2 20 21 and may be applied to intravascular contrast
agents and a well-defined input function. MR studies have produced very
good results in animal models.13 14 17 However, several
limitations appertain in patients. Currently available contrast agents
rapidly leak out of the vascular bed and diffuse into the extracellular
space, such as the myocardium. Thus, the resultant signal
intensity (SI)-time curve is a combination of perfusion and diffusion,
both of which are influenced by blood flow.22 23 The early
part of the SI-time curve is mainly influenced by perfusion and to a
lesser extent by diffusion, and the latter parts are increasingly
influenced by diffusion. Another problem of the -variate fit is the
need for 6 data points during the washout (downslope) of the contrast
agent to allow for reliable calculation.18 To guarantee
such a downslope, a small and compact contrast agent bolus must pass
through the myocardium. In the experimental animal, this
can be achieved by left atrial injection. However, in patients this may
not be possible, particularly as ischemic myocardial segments
show a slower passage of the contrast agent,24 which
results in a stronger influence of diffusion and a less pronounced or
even nonexistent downslope.
To circumvent these problems with a -variate function and to
minimize the influence of diffusion on the results, a linear fit of the
upslope of the SI-time curves rather than mean transit time, maximal
signal intensity, downslope, or time to maximal signal intensity was
used for the present analysis. The linear fit was highly
reproducible, with excellent interobserver and intraobserver
variabilities, and could be performed in 97% of all evaluated
myocardial segments.
To achieve a compact bolus and good myocardial SI-time curves, only a small amount of contrast agent was used and injected through a central vein catheter. Patients with significant valvular disease or low ventricular ejection fraction were excluded from the study to improve bolus arrival in the myocardium. The placement of a central venous catheter is not practical for routine diagnosis. However, because the upslope of the SI curves was used to calculate myocardial perfusion reserve, a peripheral gadolinium-DTPA injection should be feasible. Our first observations with the use of peripheral injection underline this expectation.
The myocardial perfusion reserve for segments supplied by stenotic coronary arteries and segments supplied by nonstenotic coronary arteries found in this study are in good agreement with values reported previously with PET2 20 24 25 26 or Doppler coronary flow reserve measurements when segments remote to the territory of a coronary artery stenosis in patients with single-vessel disease were studied.27 28 The resultant cutoff value of 1.5 for myocardial perfusion reserve is less than the lower normal value found in the literature measured by different techniques in healthy control subjects.20 21 24 29 This can be explained by the reduced vasodilatory response and thus reduced myocardial perfusion reserve in segments supplied by nonstenotic coronary arteries in patients with coronary artery disease when compared with healthy control subjects. The goal of the study was to differentiate the segments supplied by stenotic coronary arteries from those supplied by nonstenotic coronary arteries. This was successfully achieved by the cutoff value used in this study. Another reason for the lower cutoff value, when compared with the literature, was the use of dipyridamole for vasodilation, which is less potent, shows a more variable response than adenosine,30 and might result in submaximal vasodilation. In general, there is a wide range of myocardial perfusion reserve values in the literature that can be attributed to methodological reasons and to the interindividual physiological variation of myocardial perfusion reserve that is seen even in healthy subjects, which is mainly the result of variations of myocardial perfusion at rest. This is influenced by the resistance of the small vessels, collateralization, hemodynamic parameters, perfusion pressure, intramyocardial pressure, the severity of the coronary artery stenosis, and age.24 29 31
In this study, coronary angiography was used as the reference
method for the detection of coronary artery stenosis.
Because coronary angiography detects luminal morphology rather
than the functional significance of a stenosis,
"false-positive" MR results might in fact be "false-negative"
angiograms. Three of the 7 segments that had a "false-positive"
reduction of myocardial perfusion reserve showed 1 stenosis
<75% area reduction of the corresponding coronary artery on
quantitative angiography. Furthermore, 2 false-positive segments were
found in 1 patient with diffuse atherosclerosis of the
nonstenotic coronary arteries.
Limitations
The major limitation of this study was the use of a single-slice
technique. Thus, the myocardium was only partially
visualized and significant myocardial ischemia might have been
missed. However, only patients with 75% stenosis of a major
coronary artery were regarded as having significant
coronary artery disease. Thus, rather large ischemic
areas are to be expected, which explains the high sensitivity of the
present study. In future studies, the value of multislice
techniques32 must be assessed.
A possible limitation is the combined use of nonischemic segments from patients with single-vessel disease and patients without significant coronary artery disease for the definition of the ischemic threshold. However, myocardial perfusion reserve in nonischemic segments of patients with single-vessel disease and patients without significant stenosis did not differ significantly, probably a result of the fact that the latter also had coronary atherosclerosis. In addition, these patients often show a high coronary risk profile and thus must be differentiated from patients without coronary artery disease.
In the current study, we have shown that MR first-pass perfusion measurements yield a high diagnostic accuracy for the detection of coronary artery disease. Myocardial perfusion reserve can be easily and reproducibly determined from the upslope of the SI-time curves.
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Methods |
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TopAbstractIntroductionResultsDiscussionMethodsReferences |
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Patients
The study population consisted of 60 patients (Table 2
) who were referred for coronary
angiography. Written and informed consent was obtained from all
patients.
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Validation
Initially, 15 patients with single-vessel disease and 5
patients with chest pain but without significant stenoses of
the coronary arteries were examined to define the cutoff values
in perfusion measurements for the detection of significant
coronary artery stenosis (group A). This group served
for the validation of the technique and for the determination of
interobserver variability and intraobserver variability.
Determination of Diagnostic Accuracy
The subsequent 40 patients with suspected single-vessel or
double-vessel disease, who were referred for a coronary
angiography because of new chest pain or progressive symptoms, were
prospectively examined by the use of the previously defined threshold
value (group B). In this group, the diagnostic accuracy of
MR perfusion reserve measurement in comparison with angiography was
assessed.
Patients were excluded if they were <18 years old or had a history of
myocardial infarction, unstable angina, hemodynamic
relevant valvular disease, ventricular extrasystole
Lown class III, atrial fibrillation, ejection fraction <30%, blood
pressure >160/95 mm Hg or <100/70 mm Hg, obstructive
pulmonary disease, claustrophobia, or contraindications such as
incompatible metal implants. Antianginal medication was stopped, and
patients refrained from caffeine-containing beverages for 12 hours
before the examination.
Coronary Angiography
After the MR examination, all patients underwent left-sided
cardiac catheterization and biplane selective
coronary angiography by the Judkins technique. Coronary
stenoses were filmed in the center of the field from multiple
projections, and as much as possible overlap of side branches and
foreshortening of relevant coronary stenoses was
avoided. Coronary angiograms were quantitatively assessed with
the QANSAD-QCA system (ARRI), for high-grade coronary artery
stenoses (75% area stenosis). The examiner was
blinded to the MR examination.
MR Perfusion Measurements
The patients were examined in the supine position with a 1.5-T,
whole-body MR tomograph (ACS NT, Philips), with the use of a 5-element,
phased-array cardiac surface coil after the placement of a central vein
catheter in the superior vena cava through the right cubital vein. The
position of the catheter was controlled with x-ray and corrected if
needed. After 2 rapid surveys to determine the exact position and axis
of the left ventricle, a short-axis slice at the height of the origin
of the papillary muscles was chosen for perfusion imaging with an
ECG-triggered, T1-weighted, inversion recovery single-shot turbo
gradient echo sequence (prepulse delay 360 ms, acquisition duration 360
ms, flip angle 15°, TE 1.7 ms, TR 9 ms). Slice thickness was 8
mm, with a spatial resolution of 1.7x1.9 mm. During a short
expiratory breathhold of 10 heart beats, 10 native dynamic images were
acquired. During a second expiratory breathhold, a bolus of 0.025
mmol gadolinium DTPA/kg body wt (Magnevist, Schering AG) was rapidly
injected by hand and flushed through with 10 mL of 0.9% NaCl. Sixty
dynamic images (1 image per heart beat) were acquired during the first
and second passes of the contrast agent. Care was taken to achieve
breath holding during the first pass of the contrast agent to minimize
breathing artifacts during the upslope. During the acquisition of
later images, the patients were allowed to take single deep breaths as
needed. (Figure 4).
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After 15 minutes, to allow for the clearance of the first contrast agent injection, 0.56 mg dipyridamole/kg body wt was administered for 4 minutes. During dipyridamole infusion, an ECG rhythm strip was continuously acquired and blood pressure was measured once per minute. The dipyridamole infusion was discontinued prematurely on patient request or when progressive or severe angina, dyspnea, decrease in systolic pressure >40 mm Hg, severe arrhythmias, or other adverse effects occurred. Aminophylline was administered as required.
Image Analysis
In all images, the endocardial and epicardial contours were
traced by an examiner blinded to the angiographic results by the use of
a custom-written program on a Sun-Sparc workstation and corrected
manually for changes of diaphragmatic position caused by breathing or
diaphragmatic drift. The left ventricular cavity and the
pericardium were excluded from the myocardial contours. The
myocardium was then divided into 6 equiangular segments and
numbered clockwise beginning with the anterior septal insertion of the
right ventricle. An additional region of interest was placed within the
cavity of the left ventricle, excluding myocardial segments or
papillary muscles (Figure 5). Images
acquired after premature ventricular beats or insufficient
cardiac triggering were excluded from the analysis to guarantee
steady-state conditions. SI was determined for all dynamics and
segments (Figure 5). The native SI was subtracted and the
upslope of the resulting SI-time curve was determined by the use of a
linear fit. To allow the comparison of different SI curves, possible
differences of the input function must be considered. The results of
the myocardial segments were corrected for the input function by
dividing the upslope of each myocardial segment through the upslope of
the left ventricular SI curve, which was regarded as a
measure of the input function. Perfusion reserve was calculated by
dividing the results at maximal vasodilation by the results at
rest.33
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To determine intraobserver and interobserver variabilities, 200 segments were reevaluated by the same examiner and by a different examiner.
Two experienced observers, blinded to the MR examination, decided by
visual examination which of the 6 myocardial segments was supplied by
which coronary artery. Segments 1 and 6 were always assigned to
the LAD, segment 3 to the LCX, and segment 5 to the RCA. Segment 2 was
either assigned to the LAD or the LCX, which was dependent on the
angiographic appearance; segment 4 was assigned in the same manner
either to the LCX or to the RCA (Figure 5
).
Validation
In group A, the segment with the lowest myocardial perfusion
reserve within the territory of the stenotic coronary
artery was defined as ischemic. All segments of the patients
without significant coronary artery disease and the
contralateral segment opposite to the ischemic segment in the
15 patients with single-vessel disease were defined as
nonischemic. The absolute upslope at rest, after
dipyridamole infusion, as well as myocardial perfusion
reserve of ischemic and nonischemic segments, were
compared. The cutoff value was defined as the mean perfusion reserve
minus 2 SD of all nonischemic segments.
Determination of Diagnostic Accuracy
In group B, myocardial perfusion reserve was calculated for all
segments. If the myocardial perfusion reserve was less than the defined
cutoff value, the segment was classified as pathological; if it was
more than the cutoff value, it was defined as normal. If 1 segment
within the territory of a coronary artery was found to be
ischemic, MR was regarded as positive for that region.
Statistical Analysis
All data are given as mean±1 or 2 SD; a value of
P<0.05 was regarded as statistically significant. An
unpaired 2-tailed Student’s t test was used for differences
between examinations at rest and after stress in myocardial segments
supplied by stenotic and nonstenotic coronary
arteries. A linear regression analysis was performed to
determine intraobserver and interobserver variabilities. The relative
difference of repeated analysis was calculated by dividing the
difference of the 2 results by the mean of the
2.34
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Acknowledgments |
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This study was supported in part by Philips Medical Systems, Hamburg, Germany, and Philips Medical Systems, Best, The Netherlands. We thank Thomas Büge and Susan Wegner for adaptation and optimization of the analysis software.
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Footnotes |
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The Methods section of this article can be found at http://www.circulationaha.org
Received July 2, 1999; revision received October 8, 1999; accepted October 21, 1999.
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