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Published online before print August 30, 2002, 10.1148/radiol.2251011377
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(Radiology 2002;225:104-112.)
© RSNA, 2002

Experimental Studies

Single-Vessel Coronary Artery Stenosis: Myocardial Perfusion Imaging with Gadomer-17 First-Pass MR Imaging in a Swine Model of Comparison with Gadopentetate Dimeglumine1

Bernhard L. Gerber, MD, PhD, David A. Bluemke, MD, PhD, Bennett B. Chin, MD, Raymond C. Boston, PhD, Alan W. Heldman, MD, João A. C. Lima, MD and Dara L. Kraitchman, VMD, PhD

1 From the Departments of Medicine, Division of Cardiology (B.L.G., A.W.H., J.A.C.L.), and Radiology (D.A.B., B.B.C., D.L.K.), Johns Hopkins Medical Institutions, 601 N Caroline St, Suite 4231, Baltimore, MD 21287-0845; and Department of Veterinary Medicine, University of Pennsylvania, Kennett Square, Pa (R.C.B.). From the 2000 RSNA scientific assembly. Received August 13, 2001; revision requested October 10; final revision received April 2, 2002; accepted April 12. Supported by grants from Schering, Berlin, Germany, and Berlex Laboratories, Wayne, NJ. Address correspondence to D.L.K. (e-mail: dara@mri.jhu.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate the ability of Gadomer-17 to depict perfusion defects in a closed-chest swine model of single-vessel coronary artery disease.

MATERIALS AND METHODS: Twelve pigs underwent closed-chest placement of a flow reducer for 70%–90% luminal stenosis in the proximal left anterior coronary artery. Magnetic resonance (MR) perfusion imaging with Gadomer-17 and gadopentetate dimeglumine, microsphere blood flow (MBF) testing, and technetium 99m (99mTc) 2 methoxyisobutylisonitrile (MIBI) single photon emission computed tomography (SPECT) were performed during dipyridamole vasodilation. Comparisons of percentage signal intensity (SI) increase (PSIC) in remote and ischemic myocardium were made with repeated measurements analysis of variance after injection of both tracers.

RESULTS: Perfusion defects and reduced PSIC in the anterior ischemic versus the inferior remote myocardium could be identified after injection of both Gadomer-17 (PSIC, 66% ± 30 [mean ± SD] vs 100% ± 32, respectively; P < .001) and gadopentetate dimeglumine (PSIC, 49% ± 31 vs 81% ± 43, respectively; P < .005). The size of perfusion defect depicted with both tracers was highly correlated with defect size at 99mTc MIBI SPECT (r = 0.69, P < .05 for Gadomer-17 and r = 0.60, P = .05 for gadopentetate dimeglumine) and with areas of reduced MBF (r = 0.70, P < .05 for Gadomer-17 and r = 0.80, P < .05 for gadopentetate dimeglumine). PSIC also correlated with MBF (r = 0.89, P < .001 for Gadomer-17 and r = 0.75, P < .001 for gadopentetate dimeglumine). Gadomer-17 allowed differentiation of ischemic from nonischemic myocardium, as demonstrated by reduced PSIC (PSIC, 48% ± 38 vs 72% ± 31, respectively; P < .001) until 20 minutes after contrast material injection. In contrast, differentiation of ischemic from nonischemic myocardium was possible only until 55 seconds after injection of gadopentetate dimeglumine (PSIC, 36% ± 24 vs 56% ± 27, respectively; P < .005) but not at any time point thereafter.

CONCLUSION: With the study conditions, Gadomer-17 provided more prolonged differentiation of ischemic from remote myocardium than that with gadopentetate dimeglumine.

© RSNA, 2002

Index terms: Animals • Heart, perfusion, 511.12144 • Magnetic resonance (MR), contrast enhancement, 511.12143 • Magnetic resonance (MR), contrast media, 511.12143 • Myocardium, blood supply, 511.76, 511.771 • Myocardium, MR, 511.121412, 511.12143 • Myocardium, SPECT, 511.12162


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
There is considerable interest in the functional assessment of severity of coronary artery stenosis with magnetic resonance (MR) perfusion imaging (1–3). The potential for MR perfusion imaging to help distinguish normal from ischemic myocardium in the presence of flow-limiting coronary artery stenosis has been shown both experimentally in animals (4–6) and in the clinical setting (2,3,7–12).

Most conventional gadolinium-based MR perfusion tracers, such as gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ), have a low molecular weight that allows rapid diffusion from the vascular to the extravascular space (9,13). Therefore, perfusion defects appear only as transient phenomena (2,9). Thus, fast MR imaging techniques are necessary to depict perfusion defects during the first passage of the contrast agent before extravasation to the extracellular space. The demands for rapid imaging to achieve high temporal resolution make spatial evaluation of the entire left ventricle challenging (14). Consequently, contrast agents with a higher molecular weight, with limited distribution to the intravascular space, might provide better and more prolonged depiction of myocardial perfusion defects than that with extravascular agents (15,16).

Gadomer-17 (Schering, Berlin, Germany) is a polymeric molecule from a new class of gadolinium-containing MR contrast agents. The compound has a dendrimeric structure with an apparent molecular weight of 30–35 kD, which limits distribution to the vascular space and prolongs renal clearance (17,18). The purpose of this study was to evaluate the ability of this contrast agent to depict perfusion defects in a closed-chest swine model of single-vessel coronary artery disease.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Animal Model
Twenty-one female farm pigs (27–35 kg) underwent surgery to produce a closed-chest model of single-vessel coronary artery stenosis (19). The animal studies were approved by the institutional animal care and use committee and were performed in compliance with National Institutes of Health guidelines. Of the 21 animals prepared, eight died suddenly before undergoing MR imaging. Another animal died in the magnet after completing the Gadomer-17 perfusion study but before undergoing gadopentetate dimeglumine perfusion imaging. The remaining 12 animals successfully completed the entire protocol of MR imaging and single photon emission computed tomography (SPECT).

Animals were fasted for 24 hours and received aspirin (325 mg) and diltiazem hydrochloride (180 mg sustained release) orally the evening before the experiment. After premedication with acepromazine maleate (0.2 mg per kilogram of body weight) and ketamine hydrochloride (15–20 mg/kg) intramuscularly, the pigs were anesthetized with sodium pentothal (25 mg/kg) intravascularly, intubated, and mechanically ventilated with an admixture of 1%–2% isoflurane and 100% oxygen. Femoral and carotid artery venotomies were performed for placement of 8- and 10-F introducers (Medi-Tech/Boston Scientific, Natick, Mass), respectively. Heparin was injected at an initial dose of 10,000 IU intravenously, and the injections were repeated every hour at a dose of 5,000 IU intravenously to maintain anticoagulation throughout the entire study. Then, a 6-F pigtail catheter (Cordis, Diamond Bar, Calif) was advanced via the femoral artery, with fluoroscopic guidance, into the left ventricle to allow injection of radiolabeled microspheres for measurement of regional myocardial blood flow. In addition, before coronary catheterization, a continuous infusion of lidocaine hydrochloride (2 mg/kg/min) was initiated.

For placement of the coronary flow reducer, the left main coronary artery was engaged with an 8-F right Judkins catheter (Cordis), and a 0.018-inch coronary guide wire was placed in the distal left anterior descending coronary artery. The guiding catheter was then removed. Then, a nylon flow reducer fitting with an inner diameter 0.7–1.0 mm was advanced and wedged in the proximal left anterior descending coronary artery by using a coronary angioplasty balloon to create a stenosis of approximately 70%–90% of the vessel diameter. The guide wire and angioplasty balloon were then removed. The flow reducer fitting consisted of a tapered nylon cylinder with a maximum outer diameter of 3 mm and a specified inner diameter of 0.7–1.0 mm. Coronary angiograms were obtained at baseline and after stenosis placement (Fig 1) to confirm placement of the device and to determine the degree of coronary stenosis.



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  		Figure 1a. (a) Nylon coronary flow reducer (arrow) on guide wire adjacent to coronary angioplasty balloon. (b) Representative angiogram in the left anterior oblique view shows 90% stenosis (arrow) of the proximal left anterior descending coronary artery after insertion of the device.

 


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  		Figure 1b. (a) Nylon coronary flow reducer (arrow) on guide wire adjacent to coronary angioplasty balloon. (b) Representative angiogram in the left anterior oblique view shows 90% stenosis (arrow) of the proximal left anterior descending coronary artery after insertion of the device.

 
Study Protocol
After the coronary stenosis was created, the animals were brought to the MR facility to undergo MR perfusion imaging with Gadomer-17 and gadopentetate dimeglumine during pharmacologic vasodilation. Maximum hyperemic vasodilation was induced with a standard dipyridamole stress test consisting of an intravenous infusion of 0.56 mg/kg/min dipyridamole for 4 minutes. During vasodilation, blood pressure was stabilized with concurrent infusion of phenylephrine hydrochloride. Seven minutes after the start of dipyridamole infusion, 1 mCi/kg 99mTc MIBI was injected intravenously, followed immediately by an intravenous bolus injection of 0.05 mmol/kg Gadomer-17 and simultaneous MR perfusion acquisition. The Gadomer-17 injection was performed with a power injector at a rate of 5 mL/sec and followed by a 20-mL saline flush.

After 1 hour for clearance of the contrast agent from the blood, the dipyridamole stress was repeated, and MR perfusion images were acquired immediately after an intravenous bolus injection of 0.1 mmol/kg gadopentetate dimeglumine. The injection was performed with a power injector (Medrad, Indianola, Pa) at the same rate of 5 mL/sec as was used with Gadomer-17. Regional blood flow was determined after bolus injection of 2 x 106 radioactive microspheres (tin 113, scandium 46, cobalt 57, niobium 95, and ruthenium 114; Perkin Elmer Life Sciences, Boston, Mass), with a mean diameter of 15.5 µm, into the left ventricular cavity. A reference blood sample was obtained from the femoral introducer sheath from 30 seconds before left ventricular injection until 120 seconds after bolus injection. Microsphere blood flow (MBF) was determined at three time points during the study: (a) before cardiac catheterization, (b) 5–15 minutes after creation of the coronary stenosis, and (c) during the dipyridamole stress test.

After completion of the MR study, the animals were transported to the nuclear medicine suite to undergo gated SPECT of the heart. Thereafter, the animals were euthanized humanely with an overdose of sodium pentobarbital. The hearts were arrested by means of intravenous injection of concentrated potassium chloride, excised, and sliced into five to six regularly spaced short-axis slices (approximately 1 cm thick). Slices were then incubated in 2% 2,3,5–triphenyltetrazolium chloride (TTC) solution for 20 minutes at 37°C to define infarct size.

After formalin fixation, samples from the left ventricle were collected from three myocardial layers (endocardium, midventricle, and epicardium), weighed, and counted in a gamma emission well spectrometer (model 5986; Packard Bioscience, Downers Grove, Ill) along with reference blood samples to calculate regional MBF according to standard techniques. The ischemic area was computed as the percentage of left ventricular area with less than 60% maximum MBF during hyperemia.

MR Imaging and Analysis
MR imaging was performed with a 1.5-T MR imager (CV/i; GE Medical Systems, Milwaukee, Wis), with the animals lying in the right decubitus position. Images were acquired with a phased-array surface coil wrapped around the chest wall. Electrocardiographic and arterial pressure findings were monitored throughout the imaging protocol.

After localization of the heart with transverse and oblique scout images, contiguous stacks of short-axis images (of five to six slices) were prescribed to cover the entire heart from base to apex. MR perfusion images were acquired with an electrocardiography-gated breath-hold interleaved saturation-recovery gradient-echo echo-planar MR imaging pulse sequence (20), which provided coverage of the entire myocardium every other heartbeat. Imaging parameters included the following: 6.2/1.2/160 (repetition time msec/echo time msec/inversion time msec), echo train length of four, 128 x 128 image matrix interpolated to 256 x 256 pixels, 20° flip angle, 28 x 21-cm field of view, 8-mm section thickness, 2-mm section spacing, 90° saturation pulse, 125-kHz bandwidth. After baseline images were acquired, a first-pass MR perfusion image consisting of 40 phases (approximately 60 seconds) was acquired, starting with contrast agent infusion during dipyridamole-induced hyperemia. Additional images (10 phases) were acquired intermittently every 5 minutes until 20 minutes after contrast agent injection. To minimize respiratory motion, the ventilator was paused at end expiration for each imaging acquisition.

MR perfusion images were analyzed off-line by using a workstation (Sun; Sun Microsystems; Santa Clara, Calif) with custom-designed software (Cine; GE Medical Systems). Short-axis images were sorted according to section location and acquisition time. The left ventricular endocardial and epicardial contours were traced manually by one author (B.L.G.), and the left ventricular myocardium was divided into six circumferential regions of interest by using the anterior insertion of the right ventricle as an anatomic landmark. Percentage SI change versus time curves for the anterior (ischemic) and posterior (remote) wall region of interest and left ventricular cavity were computed as PSIC = [(SIt - SI0)/SI0] x 100, where SIt is SI at time t and SI0 is SI before injection of contrast agent. Computer-generated circumferential profiles of SI were used to determine the size of the perfusion defect for both tracers. Each short-axis section of the left ventricle was divided into 36 serial segments with 10° angles. SI within each segment was expressed in relative terms as percentage of maximal SI. Sectors with less than 60% maximal peak SI were considered to represent a perfusion defect. The size of the left ventricular perfusion defect (percentage) was computed as the ratio of sectors with reduced perfusion over all sectors.

SPECT Imaging and Analysis
After MR imaging, gated SPECT was performed with a triple-headed gamma camera (Triad; Trionix, Twinsburg, Ohio) with high-resolution collimators. Acquisition parameters included the following: 360° acquisition, 3° per stop, 40 heartbeats per projection, and eight time intervals per cardiac cycle. Images were reconstructed by means of filtered backprojection by using a Butterworth filter with a cutoff frequency of 0.65 cycles per centimeter and a roll-off of 4.0 without scatter and attenuation correction. SPECT images were reoriented and interpolated in the short-axis plane for comparison with MR images. The short-axis resectioned volume consisted of 16 sections of 128 x 128 pixels with a 3.56-mm3 voxel. Analysis of SPECT images was performed by one author (B.L.G.) by using the user interactive program Mediman (21). Percentage perfusion defect was computed from circumferential profiles, as described for MR imaging, as the ratio of sectors with less than 60% maximal activity over all analyzed sectors.

Statistical Analysis
Values are reported as means plus or minus SDs. One-way analysis of variance was used to compare the area of perfusion defect between Gadomer-17, gadopentetate dimeglumine, 99mTc methoxyisobutylisonitrile (MIBI) SPECT, and microspheres. Regression analysis was used to compare maximum PSIC between both tracers and microsphere flow. Repeated measurement analysis of variance was used to compare PSIC at different time points between ischemic and nonischemic areas and between both perfusion tracers. In addition, the analysis of variance was also performed with a group variable that coded for the flow reducer vessel patency (ie, occluded or patent) at postmortem examination. Individual comparisons were performed with a post hoc Bonferroni test. All tests were two sided, and differences with a P value of less than .05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Experimental Preparation and Hemodynamics
Hemodynamics during the experimental protocol are reported in Table 1. Despite infusion of phenylephrine hydrochloride, systolic blood pressure decreased slightly during dipyridamole infusion.


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  		TABLE 1. Hemodynamic Findings during Experimental Protocol

 
Pathologic and MBF Results
Pathologic and MBF results are reported in Table 2. Different outcomes were observed in the animals after stenosis placement. In four animals, TTC staining demonstrated extensive transmural anterior myocardial infarction (40% ± 8 of total left ventricular area). These four animals had been resuscitated from ventricular fibrillation shortly after stenosis placement and had severe reduction of anterior MBF at rest. The coronary flow reducer was occluded in these four animals at postmortem examination. The remaining eight animals had a patent flow reducer at postmortem examination and no significant reduction of MBF at rest in the anterior region. These eight animals had either no infarction (n = 5) or only small areas of patchy subendocardial necrosis (4% ± 2 of total left ventricular area, n = 3). Coronary stenosis severity tended to be slightly greater and resting and hyperemic MBF tended to be slightly lower in the animals with subendocardial necrosis than in infarct-free animals. These differences might have led to the occurrence of such necrosis in these animals.


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  		TABLE 2. Angiographic, Pathologic, and MBF Results for Animals

 
MBF during dipyridamole infusion was significantly reduced in the anterior region of all 12 animals (to 42% ± 35 of remote levels, P < .001). This finding demonstrates a flow-limiting effect of the flow-reducer during maximum vasodilation.

Perfusion Defect at Contrast Material–enhanced MR Imaging and 99mTc MIBI SPECT
All animals had visual perfusion defects in the anterior and septal regions at MR perfusion imaging during hyperemia after injection of Gadomer-17 or gadopentetate dimeglumine (Fig 2). The location of the defect corresponded to the location of the perfusion defect detected on 99mTc MIBI SPECT images.



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  		Figure 2. MR perfusion images acquired with a saturation-recovery fast gradient-echo sequence with echo-planar readout (6.2/1.2/160 [repetition time msec/echo time msec/inversion time msec], field of view of 28 x 21 cm, flip angle of 20°, and echo train length of four) with Gadomer-17, gadopentetate dimeglumine (Gd-DTPA), and 99mTc MIBI SPECT show a perfusion defect (arrows) in the anterior region during pharmacologic vasodilation with dipyridamole.

 
There was an excellent correlation between the size of the perfusion defect measured at peak enhancement with Gadomer-17 or gadopentetate dimeglumine (r = 0.79, P < .005). The size of the perfusion defect depicted with both MR perfusion tracers also correlated well with the extent of the hypoperfused area depicted with microspheres (r = 0.70, P < .05 for Gadomer-17 and r = 0.80, P < .05 for gadopentetate dimeglumine). In addition, the MR perfusion defect size correlated well with the defect measured on 99mTc MIBI SPECT images (r = 0.69, P < .05 for Gadomer-17 and r = 0.60, P = .05 for gadopentetate dimeglumine). There was no significant difference in measured perfusion defect size with Gadomer-17 or gadopentetate dimeglumine (30% ± 15 vs 33% ± 18). The extent of the perfusion defect identified with both MR tracers was, however, significantly larger than the size of the defect with SPECT (20% ± 20, P < .05 vs both Gadomer-17 and gadopentetate dimeglumine [Fig 3]) but was smaller than the hypoperfused area with microspheres (53% ± 20, P < .001).



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  		Figure 3. Bar graph depicts mean perfusion defect size (area with less than 60% of maximum peak SI) with Gadomer-17 or gadopentetate dimeglumine (Gd-DTPA) perfusion MR imaging and with 99mTc MIBI SPECT. Error bars = SDs, * = P < .05 compared with Gadomer-17 or gadopentetate dimeglumine. The extent of the perfusion defect was similar with Gadomer-17 or gadopentetate dimeglumine but was significantly larger as measured with both MR perfusion tracers than the size of the defect measured with 99mTc MIBI SPECT.

 
SI versus Time Curves in Remote Myocardium after Injection of Gadomer-17 or Gadopentetate Dimeglumine
Figure 4 shows a typical example of an SI versus time curve in an animal after injection of Gadomer-17 or gadopentetate dimeglumine. Injection of Gadomer-17 resulted in a slightly larger peak increase of contrast enhancement in remote nonischemic myocardium than that with gadopentetate dimeglumine (PSIC, 100% ± 32 vs 81% ± 43, respectively; difference not significant). As expected, Gadomer-17 had a smaller peak myocardium-to-blood ratio of PSIC in remote nonischemic myocardium than that with gadopentetate dimeglumine (32 ± 7 vs 62 ± 2, respectively; P < .001). This finding reflects the smaller volume of distribution of the intravascular contrast agent compared with that of the extravascular agent. Furthermore, injection of Gadomer-17 resulted in a longer persistence of contrast enhancement in remote myocardium than that with gadopentetate dimeglumine (72% ± 46 vs 25% ± 23 of peak myocardial PSIC 15 minutes after contrast agent injection, respectively; P < .05). This finding reflects prolonged intravascular retention of the dendrimeric compound compared with that of the extravascular contrast agent.



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  		Figure 4a. Line graphs depict time-activity curves with (a) Gadomer-17 or (b) gadopentetate dimeglumine in a representative animal with stenosis without infarct of the proximal left anterior descending coronary artery. Results with both tracers demonstrate higher SI increase in the inferior remote myocardium than in the anterior myocardium. This finding corresponds to the vascular bed being subtended by the coronary flow reducer.

 


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  		Figure 4b. Line graphs depict time-activity curves with (a) Gadomer-17 or (b) gadopentetate dimeglumine in a representative animal with stenosis without infarct of the proximal left anterior descending coronary artery. Results with both tracers demonstrate higher SI increase in the inferior remote myocardium than in the anterior myocardium. This finding corresponds to the vascular bed being subtended by the coronary flow reducer.

 
PSIC in Ischemic versus Remote Myocardium after Injection of Gadomer-17 or Gadopentetate Dimeglumine
When compared with remote myocardium in all 12 animals, the ischemic myocardium in the anterior wall had lower peak contrast enhancement after injection of Gadomer-17 (PSIC, 66% ± 30 vs 99% ± 32, respectively; P < .001) or gadopentetate dimeglumine (PSIC, 49% ± 31 vs 81% ± 43, respectively; P < .005) than that of nonischemic myocardium in the inferior wall. In addition, compared with remote myocardium, ischemic myocardium in the anterior wall that was subtended by the stenosis of the left anterior descending coronary artery also manifested a slower upslope of PSIC than that in remote myocardium after injection of Gadomer-17 (8% ± 2 vs 13% ± 5, respectively; P < .001) or gadopentetate dimeglumine (6% ± 7 vs 10% ± 7, respectively; P < .05).

Peak PSIC during hyperemia in ischemic and remote myocardium after injection of Gadomer-17 or gadopentetate dimeglumine were compared with relative MBF in the same regions. Correlation plots are shown in Figure 5. Peak PSIC with both tracers correlated well with MBF; however, the correlation coefficient was slightly higher for Gadomer-17 (r = 0.89, P < .001) than for gadopentetate dimeglumine (r = 0.75, P < .001).



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  		Figure 5a. Scatterplots depict correlation between peak PSIC in ischemic and remote myocardium versus relative MBF after injection of (a) Gadomer-17 or (b) gadopentetate dimeglumine (Gd-DTPA). Peak PSIC with both perfusion tracers was highly correlated with relative MBF measurements.

 


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  		Figure 5b. Scatterplots depict correlation between peak PSIC in ischemic and remote myocardium versus relative MBF after injection of (a) Gadomer-17 or (b) gadopentetate dimeglumine (Gd-DTPA). Peak PSIC with both perfusion tracers was highly correlated with relative MBF measurements.

 
Persistence of Perfusion Defects in Ischemic Myocardium with Gadomer-17 or Gadopentetate Dimeglumine
The persistence of perfusion defects over time after first-pass imaging was evaluated at 5, 10, 15, and 20 minutes after bolus injection of both tracers. Differences in PSIC between ischemic and nonischemic myocardium persisted for longer times after injection of Gadomer-17 than those after injection of gadopentetate dimeglumine. This difference allowed more prolonged differentiation of ischemic tissue versus nonischemic tissue with Gadomer-17 than with gadopentetate dimeglumine. After injection of Gadomer-17, PSIC in ischemic myocardium remained lower than that in nonischemic myocardium until 20 minutes after injection (PSIC, 48% ± 38 vs 72% ± 31, respectively; P < .001). After injection of gadopentetate dimeglumine, differentiation was not possible any later than 1 minute after injection (PSIC, 26% ± 17 vs 40% ± 16, respectively, at 5 minutes after injection; difference not significant) (Fig 6).



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  		Figure 6a. Line graphs depict mean PSIC over time in ischemic ({square}) and remote ({bullet}) myocardium in all 12 animals at different time points after injection of (a) Gadomer-17 or (b) gadopentetate dimeglumine. Error bars = standard error of the mean, * = P < .05, {dagger} = P < .01, {ddagger} = P < .005 of ischemic compared with remote region. Gadomer-17 demonstrated significant reduction of PSIC in anterior ischemic versus remote myocardium until 20 minutes after injection. Such differences in PSIC could be demonstrated only until 50 seconds after injection of gadopentetate dimeglumine.

 


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  		Figure 6b. Line graphs depict mean PSIC over time in ischemic ({square}) and remote ({bullet}) myocardium in all 12 animals at different time points after injection of (a) Gadomer-17 or (b) gadopentetate dimeglumine. Error bars = standard error of the mean, * = P < .05, {dagger} = P < .01, {ddagger} = P < .005 of ischemic compared with remote region. Gadomer-17 demonstrated significant reduction of PSIC in anterior ischemic versus remote myocardium until 20 minutes after injection. Such differences in PSIC could be demonstrated only until 50 seconds after injection of gadopentetate dimeglumine.

 
Occluded versus Patent Coronary Artery
Differences in persistence of contrast enhancement between ischemic and nonischemic myocardium with both contrast agents were even more apparent, if we considered only the eight animals with normal resting perfusion, patent flow reducers, and no transmural infarcts. All these animals demonstrated perfusion defects that were transient. In these eight animals, as shown in Figure 7, differentiation of ischemic from nonischemic myocardium after injection of Gadomer-17 was possible until 5 minutes after contrast agent injection (PSIC, 68% ± 31 in ischemic vs 91% ± 26 in nonischemic myocardium, P < .001). In contrast, after injection of gadopentetate dimeglumine, such differentiation of ischemic from nonischemic myocardium was possible only until 55 seconds after injection (PSIC, 44% ± 24 vs 53% ± 31, respectively; P < .05) but not at any time point thereafter.



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  		Figure 7a. Line graphs depict mean PSIC over time in noninfarcted ischemic ({square}) and remote ({bullet}) myocardium in seven animals without transmural infarction and with maintained resting MBF at different time points after injection of (a) Gadomer-17 and (b) gadopentetate dimeglumine. Error bars = standard error of the mean, * = P < .05, {dagger} = P < .01, {ddagger} = P < .005 of ischemic compared with remote area. Gadomer-17 demonstrated significantly lower PSIC in noninfarcted ischemic compared with remote myocardium until 5 minutes after tracer injection. In contrast, such differences persisted only until 50 seconds after injection of gadopentetate dimeglumine.

 


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  		Figure 7b. Line graphs depict mean PSIC over time in noninfarcted ischemic ({square}) and remote ({bullet}) myocardium in seven animals without transmural infarction and with maintained resting MBF at different time points after injection of (a) Gadomer-17 and (b) gadopentetate dimeglumine. Error bars = standard error of the mean, * = P < .05, {dagger} = P < .01, {ddagger} = P < .005 of ischemic compared with remote area. Gadomer-17 demonstrated significantly lower PSIC in noninfarcted ischemic compared with remote myocardium until 5 minutes after tracer injection. In contrast, such differences persisted only until 50 seconds after injection of gadopentetate dimeglumine.

 
The remaining four animals that had sustained a transmural infarct due to occlusion of the flow reducers demonstrated prolonged persistence of reduced PSIC in the ischemic region that was likely related to their reduced resting MBF. This finding could be observed after injection of Gadomer-17 or gadopentetate dimeglumine. Differences persisted until 20 minutes after injection of Gadomer-17 (PSIC, 24% ± 19 in infarcted vs 64% ± 26 in noninfarcted myocardium, P < .001) and until 5 minutes after injection of gadopentetate dimeglumine (PSIC, 17% ± 7 vs 36% ± 10, respectively; P < .05) (Fig 8).



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  		Figure 8a. Line graphs depict mean PSIC over time in infarcted myocardium subtended by an occluded coronary artery ({square}) and remote myocardium ({bullet}) in four animals with transmural infarction and reduced resting MBF after injection of (a) Gadomer-17 and (b) gadopentetate dimeglumine. Error bars = standard error of the mean, * = P < .05, {dagger} = P < .01, {ddagger} = P < .005 of ischemic compared with remote area. Gadomer-17 demonstrated significantly reduced PSIC in infarcted compared with remote myocardium until 20 minutes after tracer injection. In contrast, such differences in PSIC existed only until 5 minutes after injection of gadopentetate dimeglumine.

 


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  		Figure 8b. Line graphs depict mean PSIC over time in infarcted myocardium subtended by an occluded coronary artery ({square}) and remote myocardium ({bullet}) in four animals with transmural infarction and reduced resting MBF after injection of (a) Gadomer-17 and (b) gadopentetate dimeglumine. Error bars = standard error of the mean, * = P < .05, {dagger} = P < .01, {ddagger} = P < .005 of ischemic compared with remote area. Gadomer-17 demonstrated significantly reduced PSIC in infarcted compared with remote myocardium until 20 minutes after tracer injection. In contrast, such differences in PSIC existed only until 5 minutes after injection of gadopentetate dimeglumine.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
In this study, we examined the ability of the intravascular contrast agent Gadomer-17 to depict myocardial ischemia during pharmacologic vasodilation in a porcine model of single-vessel coronary artery disease relative to the conventional extravascular contrast agent gadopentetate dimeglumine and 99mTc MIBI SPECT. The principal results of this study can be summarized as follows:

1. Gadomer-17 can depict perfusion defects in a model of single-vessel disease in pigs. The perfusion defects appeared in a location similar to that depicted with gadopentetate dimeglumine or 99mTc MIBI SPECT, but they were larger with both MR tracers than they were with the SPECT tracer.

2. The peak signal enhancement of both MR tracers correlates well with relative MBF.

3. Gadomer-17 provides more prolonged differentiation of perfusion defects than does gadopentetate dimeglumine. This finding was especially relevant in noninfarcted myocardium with maintained resting perfusion.

Gadomer-17 for the Assessment of Myocardial Perfusion
Gadomer-17 is a gadolinium-based intravascular contrast agent of intermediate molecular size that restricts the agent to the vascular space but is small enough to be freely filtered by means of glomerular filtration (17,18). Findings in earlier experimental work demonstrate the usefulness of this agent for peripheral and aortic angiography (17,18). In addition, in a prior study, this agent was used for kinetic modeling of myocardial perfusion in a small number of animals (22). However, the ability to delineate perfusion defects was not examined for Gadomer-17 versus gadopentetate dimeglumine.

In our study, injection of Gadomer-17 resulted in significant and prolonged SI enhancement of both blood pool and myocardial tissue. Findings in our study support the intravascular distribution of this contrast agent by showing a significant difference of maximal SI in myocardium compared with that in the blood pool. This difference of SI between tissue and blood persisted over time, which suggests that no significant diffusion of the contrast agent occurred from the intravascular compartment to the extravascular compartment. This finding was particularly striking in contrast to the time-activity curves of the extravascular contrast agent gadopentetate dimeglumine, which showed a higher myocardial-to-blood ratio and a more rapid elimination of the contrast agent from the blood pool. These findings are consistent with the extravascular distribution of gadopentetate dimeglumine.

Delineation of Perfusion Defect in Ischemic Myocardium
Our results demonstrate the ability of Gadomer-17 to depict myocardial ischemia during vasodilation. The concentration, and thus SI, for an intravascular contrast agent such as Gadomer-17 at any time primarily reflects regional myocardial blood volume in different regions of the heart (23). Relative changes in myocardial blood volume during hyperemic vasodilation occur in ischemic versus nonischemic vascular beds and result in changes of SI between both regions (23,24). In nonischemic myocardium, vasodilation results in an increase of myocardial perfusion without changes in myocardial blood volume (24). Conversely, in ischemic myocardium subtended by a coronary stenosis, myocardial blood volume decreases because of capillary closure secondary to a decrease in pressure downstream of the coronary stenosis (24). This decrease results in a relative reduction of the concentration of Gadomer-17 in ischemic myocardium and allow the visual differentiation of the ischemic versus the nonischemic vascular beds.

Comparison with Gadopentetate Dimeglumine
Our study findings demonstrate that the times during which perfusion defects could be identified were significantly longer for Gadomer-17 than those for gadopentetate dimeglumine. The possibility that contrast agents with higher molecular weight with intravascular distribution may provide better delineation of the ischemic zone had already been suggested in previous reports (25) but not in a direct comparison. As confirmed by our findings, agents with low molecular weight, such as gadopentetate dimeglumine, demonstrate perfusion defects only for short times after arrival of the contrast agent bolus. This most likely occurs owing to rapid diffusion of these agents from the intravascular space to the extravascular space. Because of this extravascular distribution, contrast agent concentration, and thus SI of these agents in the myocardium, depend not only on tissue blood volume and perfusion but also on the size of the extracellular compartment and the degree of capillary permeability (6). In contrast, because the molecular weight of Gadomer-17 is higher than that of gadopentetate dimeglumine, such extravascular diffusion does not occur, and contrast agent concentration and SI persistently reflect primarily changes in blood volume in different vascular beds (23,24). Consequently, a more prolonged differentiation of ischemic myocardium from nonischemic myocardium is possible with Gadomer-17; this finding reflects the duration of vasodilation induced with dipyridamole infusion.

Study Limitations
A limitation of the study design is that the animals did not receive the two contrast agents in a random order. In all studies, Gadomer-17 was injected first, followed by injection of gadopentetate dimeglumine. We expected higher extraction of the extravascular contrast agent gadopentetate dimeglumine that would have led to a greater persistence of the myocardial SI if gadopentetate dimeglumine were injected first. Thus, the Gadomer-17 injection could have been contaminated by gadopentetate dimeglumine, unless we waited a prolonged time between contrast agent injections to allow the washout of the extravascular agent. Because this is an acute model of coronary stenosis, we chose to maintain a fixed time between contrast agent injections to ensure a similar hemodynamic state and to avoid myocardial signal contamination by the extravascular agent gadopentetate dimeglumine.

Clinical Implications
The more prolonged delineation of perfusion defects with Gadomer-17 relative to that with gadopentetate dimeglumine is clinically important. The finding suggests that the former agent would require less high-temporal-resolution imaging for identification of myocardial ischemia than would the latter. The decreased temporal resolution needed for MR perfusion imaging would allow a choice of imaging techniques with more emphasis on high spatial resolution and more complete left ventricular coverage than on imaging speed.

Another potential advantage of Gadomer-17 is that after the vasodilator effect of the stress agent has subsided, the prolonged persistence of the agent in the blood pool might also allow the assessment of resting perfusion with only one contrast agent injection. This possibility is suggested by our findings, which demonstrate a persistence of perfusion defects at late times (eg, 10–15 minutes after contrast agent injection) in animals with occluded coronary arteries and reduced resting perfusion but not in animals with patent coronary arteries and maintained resting perfusion.

Finally, MR perfusion imaging with Gadomer-17 might also have important advantages relative to 99mTc MIBI SPECT. Results in our study indicate that MR perfusion imaging demonstrates significantly larger perfusion defects than does 99mTc MIBI SPECT. This finding was most likely a result of the higher spatial resolution with MR imaging compared with that with SPECT (2.1-mm-pixel resolution for MR imaging vs approximately 15-mm resolution for SPECT), which resulted in fewer partial volume effects for MR imaging than for SPECT. This finding suggests that MR perfusion imaging might be more sensitive than SPECT for delineation of smaller subendocardial perfusion defects.

Practical application: Findings in this study in an animal model of single-vessel stenosis demonstrate the potential of Gadomer-17 to reveal myocardial perfusion abnormalities during vasodilation. With the study conditions, Gadomer-17 provided more prolonged definition of perfusion defects than did gadopentetate dimeglumine; this finding suggests that the former might be superior to the latter for the prolonged visualization of perfusion defects in ischemic myocardium. In addition, findings in this study suggest that the kinetic behavior of this intravascular contrast agent might also allow differentiation of ischemic myocardium with patent coronary arteries from myocardium subtended by arteries that are occluded at rest.


   ACKNOWLEDGMENTS
 
We thank Christine Steinert, Tia Jensen, and Carolyn Magee for help in animal preparation.


   FOOTNOTES
 
Abbreviations: MBF = microsphere blood flow, MIBI = 2 methoxyisobutylisonitrile, PSIC = percentage SI increase, SI = signal intensity

Author contributions: Guarantors of integrity of entire study, B.L.G., D.L.K.; study concepts, B.L.G., D.A.B., D.L.K.; study design, B.L.G., D.A.B., A.W.H., D.L.K.; literature research, B.L.G., D.A.B., D.L.K.; experimental studies, B.L.G., A.W.H., D.L.K., B.B.C.; data acquisition, B.L.G., D.A.B., A.W.H., B.B.C., D.L.K.; data analysis/interpretation, R.C.B., B.L.G., A.W.H., D.L.K.; statistical analysis, B.L.G., R.C.B., D.L.K.; manuscript preparation, B.L.G., D.L.K.; manuscript definition of intellectual content, B.L.G., D.A.B., A.W.H., B.B.C., J.A.C.L., D.L.K.; manuscript editing, B.L.G., D.A.B., J.A.C.L., D.L.K.; manuscript revision/review, R.C.B., B.L.G., D.A.B., J.A.C.L., D.L.K., R.C.B.; manuscript final version approval, all authors.


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DISCUSSION
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