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AJR 2000; 175:1029-1033
© American Roentgen Ray Society


Assessment of Coronary Flow Reserve Using Fast Velocity-Encoded Cine MR Imaging

Validation Study Using Positron Emission Tomography

Hajime Sakuma1, Juha W. Koskenvuo2, Pekka Niemi3, Nanaka Kawada1, Jyri O. Toikka2, Juhani Knuuti4, Hanna Laine4, Markku Saraste2, Martti Kormano3 and Jaakko J. Hartiala2

1 Department of Radiology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
2 Department of Clinical Physiology, Turku University Central Hospital, 20520 Turku, Finland.
3 Department of Radiology, Turku University Central Hospital, 20520 Turku, Finland.
4 Turku PET Centre, Turku University, 20520 Turku, Finland.

Received January 21, 2000; accepted after revision March 27, 2000.

 
Address correspondence to H. Sakuma


Abstract
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Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
OBJECTIVE. Previous studies using intravascular Doppler sonography and positron emission tomography (PET) have shown that the hemodynamic significance of coronary artery stenosis can be evaluated by measuring coronary flow reserve. The purpose of this study was to assess whether MR imaging measurements of coronary flow reserve in the left anterior descending artery are comparable with those obtained with PET in the corresponding territory.

SUBJECTS AND METHODS. MR imaging and PET flow measurements were obtained in 10 healthy volunteers. Blood flow velocity in the left anterior descending artery was measured with breath-hold velocity-encoded cine MR imaging before and after IV administration of dipyridamole. The coronary flow velocity reserve measured by MR imaging was compared with the myocardial perfusion reserve in the anterior myocardium quantified on using PET and 15O-labeled water.

RESULTS. The average flow velocity reserve in the left anterior descending artery measured on MR imaging was 2.44 ± 1.14 in healthy volunteers, which was comparable with the myocardial perfusion reserve measured by PET (2.52 ± 0.84). MR imaging and PET measurements of the coronary flow reserve showed a significant correlation (r = 0.79, p < 0.01).

CONCLUSION. MR imaging measurement of the flow velocity reserve in the proximal left anterior descending artery correlates well with the myocardial perfusion reserve obtained with PET and 15O-labeled water.


Introduction
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Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
Radiographic coronary angiography has been used for evaluating coronary artery disease. However, assessment of the anatomic severity of a coronary stenosis does not adequately determine the functional significance of the lesion [1, 2]. Quantitative coronary angiography, which was designed to minimize interpretation variability, cannot reliably predict the physiologic significance of stenoses with intermediate severity [3, 4]. The hemodynamic significance of a coronary stenosis can be determined by measuring the coronary flow reserve, which is the maximal hyperemic coronary flow—baseline coronary flow ratio [5]. Previous studies using an intracoronary Doppler guidewire and positron emission tomography (PET) have shown that measurement of the coronary flow reserve is useful in evaluating the functional significance of coronary artery stenosis [6, 7], outcome of percutaneous balloon angioplasty [8], and abnormal microcirculation in patients with cardiomyopathies [9].

Flow measurement with an intracoronary Doppler guidewire has already been established as a useful technique, but it is invasive and is available only during cardiac catheterization. PET is a noninvasive technique that can measure myocardial perfusion and the perfusion reserve ratio from different regions of the myocardium at the same time. However, PET is expensive and is not widely available in clinical hospitals. These limitations have prevented widespread clinical application of intracoronary Doppler sonography and PET assessments of the coronary flow reserve.

Fast velocity-encoded cine MR imaging is an emerging application that can provide velocity time curves in the human coronary arteries with data acquisition during a single breathhold [10]. Previous studies have reported the feasibility of measuring blood flow velocity and vasodilator flow reserve in the left anterior descending (LAD) arteries in humans using fast velocity-encoded cine MR imaging [11,12,13,14].

The purpose of this study was to assess whether MR imaging measurements of the coronary flow reserve in the proximal LAD artery are comparable with those obtained with PET and 15O-labeled water in the corresponding territory that is recognized as a gold standard for measuring myocardial blood flow [15,16,17,18].


Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
Ten healthy volunteers were examined in this study (all men; mean age, 38.9 ± 12.9 years). No subject had a clinical history or evidence of coronary artery disease or other cardiac disease. Subjects of different ages and levels of sport activity were enrolled in this study to widen the range of the coronary flow reserve. Two of the subjects were very active, six were moderately active, and two were relatively inactive in sports. One subject had moderate hypercholesterolemia. The study protocol was approved by our institutional ethics committee. All subjects signed written informed consent before entering the study. The subjects were instructed to avoid large meals for 4 hr and caffeine, alcohol, and tobacco for 12 hr before MR imaging and PET studies. Mean time between MR imaging and PET studies was 8.1 ± 4.3 days. No subject experienced adverse effects with dipyridamole administration during MR imaging and PET studies.

MR Imaging Techniques
MR images were obtained with a 1.5-T clinical MR imager (Signa LX; General Electric Medical Systems, Milwaukee, WI). Subjects were placed in the supine position, and a 5-inch circular surface coil was placed on the anterior chest. ECG leads were attached to the chest for cardiac gating.

For the localization of the LAD artery, breath-hold cine MR images were acquired on coronal, axial, and oblique imaging planes as scout images. The pulse sequence used for breath-hold MR imaging flow measurement was a velocity-encoded fast gradient-echo sequence with K-space segmentation. Oblique fast velocity-encoded cine MR images were acquired on the imaging plane that was perpendicular to the LAD artery, with a section thickness of 5 mm, a TR of 16 msec, a TE of 9 msec, a field of view of 24 x 18 cm, frequency-encoding resolution of 256, phase-encoding steps of 96, a reconstructed image matrix of 256 x 192, and a pixel dimension of approximately 0.9 x 0.9 mm. Uniform radiofrequency excitation was used in this sequence, which maintains the spins in steady state, eliminates the need for dummy excitations before data collection, and enables the acquisition of data immediately after the ECG R wave trigger. Velocity encoding gradients were applied in the slice-selective direction. A velocity window of ±100 cm/sec was used for flow velocity measurement in the coronary artery because peak velocity in the LAD artery can exceed 80 cm/sec after pharmacologic stress according to a previous study [11]. Four lines in K-space were collected per trigger per segment. For each K-space image, positive and negative velocity-encoding data were acquired as a sequential pair. True temporal resolution, the time during which imaging data were acquired for each cine frame, was 128 msec. View-sharing reconstruction was used to improve the effective temporal resolution to 64 msec. Magnitude and phase-difference cine images with 9-13 temporal phases were reconstructed from the data acquired in a single breathhold (Figs. 1A and 1B).



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Fig. 1A. —27-year-old healthy male volunteer. Magnitude (A) and phase-difference (B) MR images acquired with fast velocity-encoded cine MR imaging show left anterior descending artery (arrows).

 


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Fig. 1B. —27-year-old healthy male volunteer. Magnitude (A) and phase-difference (B) MR images acquired with fast velocity-encoded cine MR imaging show left anterior descending artery (arrows).

 

After the subjects took a deep breath in and breathed out, fast velocity-encoded cine MR imaging data were acquired with suspended shallow inspiration for 20-25 sec. After obtaining MR images in the baseline state, 0.56 mg/kg of dipyridamole was injected into the antecubital vein over 4 min. The ECG and blood pressure were monitored during the administration of dipyridamole when the subjects were not in a magnetic field. Fast velocity-encoded cine MR images were obtained 2 min after finishing the dipyridamole injection.

For flow analysis, the MR imaging data were transferred from the MR imager to a PC running a LINUX operating system (Linux 5.2; Red Hat, Durham, NC). Peak flow velocity during the diastolic phase was analyzed with Xphase software (Stephan Maier, Brigham and Women's Hospital, Harvard Medical School, Boston, MA). Using magnitude images, we placed small regions of interest (ROIs) with the dimension of the vessel diameter on individual cine frames to correct in-plane movement that might occur during the cardiac cycle. We also measured flow velocity in the surrounding tissue to perform phase-offset correction. Image data were inversely Fourier-transformed to the K-space, zero-filled in both x and y directions by a factor of 4, and Fourier-transformed again to the images with a 1024 x 1024 matrix. The measurements were repeated for all cardiac phases, using a magnitude image as a reference. Maximal flow velocity in the imaging voxels in the LAD arterial lumen was calculated at each cardiac phase, and diastolic peak velocity was determined. The coronary flow reserve on MR imaging was calculated as a ratio of hyperemic to the baseline diastolic peak velocities.

PET
15O-labeled carbon monoxide was produced by a low-energy deuteron accelerator (Cyclonen 3; Ion Beam Application, Louvaine-la-Neuve, Belgium). 15O-labeled carbon monoxide is produced in a conventional way [19]. 15O-labeled water was produced by using dialysis techniques in a continuously working water module [20]. Sterility and pyrogenity tests for water and chromatographic analysis for gases were performed to verify the purity of the products.

PET data were acquired by using a tomograph (ECAT 931/08; Siemens/CTI, Knoxville, TN) with an axial resolution of 6.7 mm and in-plane resolution of 6.5 mm full width at half maximum. The subject was placed in the supine position in an PET imager with the heart in the gantry. One catheter was inserted in the antecubital vein for injecting dipyridamole and 15O-labeled water, and another catheter was inserted in the opposite side for venous blood sampling. The ECG was continuously monitored during the study. Blood pressure was monitored at 2-min intervals. After transmission scan, the 15O-labeled carbon monoxide was inhaled for 2 min through a three-way inhalation flap valve (0.14% CO mixed with room air; mean dose, 3089 ± 171 MBq). After the 15O-labeled carbon monoxide inhalation, 2 min was allowed for the 15O-labeled carbon monoxide to combine with hemoglobin in RBC before starting a 4-min static scanning. During the scanning period, three blood samples were taken at 2-min intervals. Blood radio-activity concentration was measured with a well-type detector (3MW3/3; Bicron, Newbury, OH). After completion of the the 15O-labeled carbon monoxide data collection, an additional 10 min were allowed for 15O-radioactive decay before 15O-labeled water dynamic scanning began.

Myocardial blood flow was measured at the baseline and 2 min after administration of dipyridamole (0.56 mg/kg over 4 min). 15O-labeled water (1624 ± 99 MBq) was injected and dynamic PET scanning began (every 5 sec for 30 sec, every 15 sec for 90 sec, and every 30 sec for 4 min). All data were corrected for dead time, decay, and photon attenuation, and images were reconstructed in a 128 x 128 matrix. The final in-plane resolution of the reconstructed images with Hann's filter (0.3 cycles per second) was 9.5 mm in full width at half maximum.

Regional myocardial perfusion and perfusion reserve in the anterior myocardium were calculated from the PET data. ROIs covering the anterior wall of the left ventricle were placed on four consecutive axial PET images. The ROIs were drawn on the images obtained at rest and were applied to the images obtained after dipyridamole administration. The correct placement of ROIs was confirmed for each image set. The arterial input function was obtained from the left ventricular time—activity curve using a previously validated method [17]. Values of regional myocardial perfusion (expressed in milliliters per minute per gram of tissue) were calculated in the baseline state and after dipyridamole administration according to the previously published methods using the single-compartment model [16, 17]. The coronary flow reserve on PET was defined as the ratio of baseline-to-hyperemic myocardial perfusion values in the anterior myocardium.

Statistical Analysis
All values were expressed as mean ± standard deviation. Statistical significance of the difference between MR imaging coronary flow reserve and PET coronary flow reserve was assessed with a paired two-tailed t test. Probabilities less than 0.05 were considered statistically significant. MR imaging coronary flow reserve and PET coronary flow reserve were compared using linear regression analysis.


Results
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Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
Adequate MR and PET images were obtained in the baseline state and after dipyridamole administration in all subjects. No patients experienced chest pain or significant adverse effect with dipyridamole administration. The mean systolic blood pressure, diastolic blood pressure, and heart rate in 10 healthy subjects during PET studies were 130 ± 13 mm Hg, 77 ± 11 mm Hg, and 57 ± 7 beats per minute, respectively, in the basal state and 125 ± 15 mm Hg, 72 ± 10 mm Hg, and 78 ± 9 beats per min, respectively, after dipyridamole.

The diastolic peak velocity in the proximal LAD artery measured by MR imaging was 27.5 ± 10.4 cm/sec in the baseline state and 59.8 ± 21.8 cm/sec after dipyridamole (Fig. 2). PET measurement of the myocardial perfusion per gram of myocardial mass in the LAD arterial territory was 0.64 ± 0.19 mL·min-1·g-1 in the baseline state and 1.61 ± 0.66 mL·min-1·g-1 after dipyridamole. MR imaging measurement of the coronary flow reserve in the proximal LAD artery was 2.44 ± 1.14, which was comparable with the coronary flow reserve in the anterior myocardium measured on PET (2.52 ± 0.84). MR imaging and PET assessments of the coronary flow reserve showed a significant linear correlation (Fig. 3, r=0.79, p<0.01).



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Fig. 2. —MR imaging blood flow velocity curves in left anterior descending artery in 27-year-old healthy male volunteer both in baseline state and after dipyridamole administration. Note that flow velocity in left anterior descending artery increased after dipyridamole injection.

 


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Fig. 3. —Scatter diagram for 27-year-old healthy male volunteer shows correlation between velocity flow reserve in left anterior descending artery measured on fast velocity-encoded cine MR images and myocardial perfusion reserve in anterior myocardium measured on positron emission tomography (PET). Note that MR imaging and PET assessments of coronary flow reserve showed a significant linear correlation (r=0.79, y=0.58, x+1.1).

 


Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 
The major objective of our study was to evaluate a correlation between MR imaging and PET assessments of coronary flow reserve. We observed a significant linear correlation between the coronary flow reserve in the proximal LAD artery measured on breath-hold velocity-encoded cine MR imaging and the coronary flow reserve in the anterior myocardium measured on PET and 15O-labeled water.

Assessment of Coronary Flow Reserve
Intracoronary Doppler sonography and PET have been used as reference methods for measuring coronary blood flow and flow reserve. Previous studies in patients with ischemic heart disease have reported that the coronary flow reserve is highly useful in assessing significant stenosis in the coronary artery [3,4,5,6,7]. Joye et al. [3] used an intracoronary Doppler guidewire to show that the sensitivity, specificity, and accuracy of the Doppler-determined coronary flow velocity reserve for predicting myocardial ischemia on stress 201T1 SPECT were 94%, 95%, and 94%, respectively. Flow measurement with an intracoronary Doppler guidewire has already been established as a useful technique, but it is invasive and is available only during cardiac catheterization.

PET Measurement
Use of PET and 15O-labeled water is currently recognized as the most accurate noninvasive approach for measuring regional myocardial perfusion and perfusion reserve [15,16,17,18]. 15O-labeled water has several advantages as a positron-emitting tracer for measuring blood flow in comparison with other tracers such as 13N ammonia or 82Rb [18]. Myocardial uptake and retention of 13N ammonia and 82Rb are dependent on active processes and may be affected by the metabolic status of the myocardium. In contrast, 15O-labeled water is freely diffusible. Myocardial kinetics of 15O-labeled water are simply related to blood flow and are not altered by metabolic status. In addition, its short half-life (2.1 min) allows sequential measurements of blood flow with a modest radiation dose for subjects. In contrast with an intracoronary Doppler method, PET is noninvasive and does not generate potential risk for the subjects. However, PET is an expensive, complex, and time-consuming method for determining the coronary flow reserve and is not widely available in clinical hospitals, which has limited the widespread clinical application of PET for assessing the coronary flow reserve.

MR Imaging Measurement
MR imaging has a unique potential for noninvasive measurement of coronary blood flow without radiation exposure and may have significant advantages over the existing techniques for measuring coronary blood flow and flow reserve in patients. However, MR imaging measurement of coronary blood flow has been challenging because the coronary artery is small (<3-4 mm) and subject to both cardiac and respiratory motions. With recent advances in fast MR imaging techniques, several reports have shown the feasibility of measuring coronary blood flow and flow reserve [11,12,13,14]. In particular, fast velocity-encoded cine MR imaging can show blood flow curve in the cardiac cycle with the data acquired in a single breath-hold. In addition, a previous study showed that MR imaging measurement of the coronary blood flow velocity had sufficient intraobserver and interobserver reproducibilities [11].

Validation of MR imaging blood flow measurement in the coronary artery was previously obtained in animal models using an intracoronary Doppler wire [21] or a transit time sonographic flow probe [22] as a reference. In our study, a good agreement between MR imaging and PET measurements of the coronary flow reserve was observed. Our results obtained with PET indicate that fast MR imaging blood flow measurement with dipyridamole administration is a reliable method for assessing the coronary flow reserve in humans.

Limitation of This Study
In the current MR imaging study, the coronary flow reserve was calculated as the ratio of baseline-to-hyperemic coronary blood flow velocities instead of the ratio of blood flow volume. It is possible that the use of peak velocity (cm/sec) in the MR imaging study and myocardial blood flow volume (mL·min-1·g-1) in the PET study may give different values for the coronary flow reserve if the shape of the flow versus the time curve and diameter of the coronary artery are altered after pharmacologic stress. Although flow volume could be quantified in principle by integrating the products of flow velocity and the cross-sectional area of the coronary artery over the cardiac cycle, to do so necessitates accurate flow measurements throughout the cardiac cycle and precise definition of the coronary artery border. Because of rapid cardiac movement during the systolic phase, temporal resolution of the current velocity-encoded cine MR imaging may not be sufficient for quantifying coronary blood flow volume in humans. Previous studies have reported that the flow velocity reserve measured by an intracoronary Doppler technique has good correlation with the regional myocardial perfusion reserve by PET [23]; therefore, MR imaging assessment of the coronary velocity flow reserve can be a useful parameter in clinical patients.

Conclusion
MR imaging measurement of the coronary flow reserve in the proximal LAD artery correlated well with the coronary flow reserve obtained with PET and 15O-labeled water. Breath-hold velocity-encoded cine MR imaging is a noninvasive technique to assess the coronary flow reserve in humans.


References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
 

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