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(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

Nidal Al-Saadi, MD; Eike Nagel, MD; Michael Gross, MD; Axel Bornstedt, PhD; Bernhard Schnackenburg, PhD; Christoph Klein, MD; Waldemar Klimek, MD; Helmut Oswald, PhD; Eckart Fleck, MD

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

	Abstract

Top Abstract Introduction Results Discussion Methods References

 
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

	Introduction

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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 SPECT^{1 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.

	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).

View larger version (16K): [in this window] [in a new window]   Figure 1. Interobserver and intraobserver variabilities for linear fit of upslope.

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.

View larger version (19K): [in this window] [in a new window]   Figure 2. Absolute values of upslope of ischemic (•) and contralateral control segments () 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.

View larger version (14K): [in this window] [in a new window]   Figure 3. Myocardial perfusion reserve of ischemic and control segments (contralateral segments in group A, •; all segments of 5 patients without significant coronary artery disease, ). Values are mean±1 and 2 SD.

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).

View this table: [in this window] [in a new window]   Table 1. Diagnostic Accuracy of MR Perfusion Measurements

	Discussion

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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 PET^{2 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 PET^{2 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.

	Methods

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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.

View this table: [in this window] [in a new window]   Table 2. Patient Population

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).

View larger version (63K): [in this window] [in a new window]   Figure 4. MR images of transit of gadolinium bolus through right ventricle (a), left ventricle (b), and left ventricular myocardium (c). Note compact contrast bolus, with almost complete exit of contrast agent from right ventricle when passing through left ventricle.

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

View larger version (27K): [in this window] [in a new window]   Figure 5. Six evaluated myocardial segments of left ventricular myocardium with determination of coronary artery territories for each segment and resulting SI vs time curves of myocardial segments, each compared with SI curves of left ventricular cavity. SI is given in arbitrary units.

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

	Acknowledgments

 
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.

	Footnotes

 
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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