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Infarcted Myocardium in Pigs: MR Imaging Enhanced with Slow-Interstitial-Diffusion Gadolinium Compound P760¹

¹ From the Department of Radiology (L.J.M.K., J.D., A.d.R.) and the Department of Radiology, Division of Image Processing (R.J.v.d.G.), Leiden University Medical Center, C2-S, Albinusdreef 2, 2333 ZA Leiden, the Netherlands; and Laboratoire Guerbet, Aulnaysous-Bois, France (S.B.). Received May 27, 1998; revision requested July 16; final revision received November 13; accepted January 27, 1999. Supported in part by a grant from Laboratoire Guerbet. Address reprint requests to A.d.R.

	Abstract

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
PURPOSE: To assess the value of P760, a gadolinium chelate with slow interstitial diffusion and high relaxivity, for magnetic resonance (MR) imaging of acute myocardial infarction in pigs.

MATERIALS AND METHODS: First-pass gradient-echo MR imaging and spin-echo MR imaging were performed with P760 and then with gadoterate meglumine in eight pigs with occlusive acute myocardial infarction. P760 signal intensity enhancement and clearance were compared with those of gadoterate meglumine.

RESULTS: The first-pass enhancement ratio of P760 in normal myocardium was higher than that in infarcted myocardium (1.37 ± 0.06 [SEM] vs 1.05 ± 0.03, P = .03). The myocardial first pass showed a blood pool–like curve for P760. The blood pool enhancement ratio 40 seconds after injection was higher for P760 than for gadoterate meglumine (left ventricular cavity, 1.75 ± 0.06 vs 1.45 ± 0.06, P = .009). Spin-echo MR imaging showed improved contrast between normal and infarcted myocardium after P760 administration: The ratio before contrast material administration was 0.21 ± 0.03, that at 15 minutes was 0.48 ± 0.05 (P = .002), and that at 25 minutes was 0.47 ± 0.07 (P = .003).

CONCLUSION: P760 is an MR imaging contrast agent characterized by low diffusion, a blood pool effect soon after low-dose administration, and fast elimination. This agent is useful for improved myocardial perfusion MR imaging of acute myocardial infarction.

Index terms: Contrast media, comparative studies, 511.12143 • Contrast media, experimental studies, 511.121411, 511.121412, 511.12143 • Gadolinium, 511.12143 • Heart, experimental studies, 511.121411, 511.121412, 511.12143 • Myocardium, infarction, 511.771 • Myocardium, MR, 511.121411, 511.121412, 511.12143

	Introduction

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
To improve the distinction between normal and infarcted myocardium, extracellular gadolinium-based contrast agents have successfully been used in magnetic resonance (MR) imaging (1,2). After diffusion of the contrast agent into the interstitial space, infarctions are visible as regions of high signal intensity at T1-weighted spin-echo MR imaging. In combination with a first-pass perfusion technique, information can be obtained about regional blood flow and volume during the passage of a contrast agent bolus through the myocardium (3–5).

P760 (Laboratoire Guerbet, Aulnay-sous-Bois, France [6]) is a newly designed extracellular contrast agent with two major improvements over conventional extracellular contrast agents. First, its relaxivity in plasma is seven to eight times higher than that of other currently available extracellular contrast agents (7). This means that a substantially lower dose is required to obtain similar signal intensity–enhancing effects. Second, P760 has a lower diffusion rate, which produces a transient blood pool effect, although it is not a true blood pool contrast agent. These characteristics may be clinically relevant for the functional assessment of ischemic myocardium by using MR perfusion imaging.

We performed this experimental study to examine the value of low-dose P760 for first-pass gradient-echo and delayed spin-echo MR imaging in a model of acute myocardial infarction in pigs.

	MATERIALS AND METHODS

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
Contrast Medium
P760 is a macrocyclic gadolinium chelate with a molecular mass of 5,293 Da. The size restricts fast diffusion through capillary membranes, although it is small enough to pass through the glomerular membrane, which allows rapid renal excretion. The compound, containing one gadolinium atom per molecule, is based on a tetraazacyclododecanetetraacetic acid structure that is substituted by hydrophilic bulky groups branched on the amino-acetic residues. The substituents are synthesized from a halogenated aromatic derivative. The hydrophilicity of the substituent is provided by the addition of polyhydroxylated amines on the aromatic derivative. The relaxivities of P760 are high: r1 is 24.9 L · mmol^-1 · sec^-1 and r2 is 29.4 L · mmol^-1 · sec^-1 in water at 37°C and 0.47 T. To compare, the relaxivities of gadoterate meglumine (Dotarem; Laboratoire Guerbet) are as follows: r1 is 3.8 L · mmol^-1 · sec^-1, and r2 is 4.0 L · mmol^-1 · sec^-1. Also, gadoterate meglumine has a molecular mass of 561 Da. In plasma, a dose of only 0.0065 mmol of P760 per kilogram of body weight is isoefficient with 0.05 mmol/kg gadoterate meglumine.

Surgical Procedure
All animal experiments were performed within the guidelines established by the Committee on Animal Experiments of Leiden University Medical Center, the Netherlands (8). Eight domestic female pigs with a mean weight of 31.6 kg (27.3–33.6 kg) were anesthetized with an intramuscular injection of azaperone (Stresnil; Janssen Pharmaceutica, Tilburg, the Netherlands; 2.0 mg/kg) and atropine sulfate (Atropinesulfaat, AUV Coöperatie, Cuyk, the Netherlands; 0.05 mg/kg) and an intraperitoneal injection of metomidate (Hypnodil; Janssen Pharmaceutica; 20.0 mg/kg). The animals received ventilation with a gas mixture containing 1:1 (vol:vol) oxygen and nitrous oxide and with 3%–4% isoflurane (Forene; Abbott, Amstelveen, the Netherlands) for muscle relaxation. Then they were intubated and received ventilation artificially with the same gas mixture but with 1% isoflurane. A 4-mg bolus of pancuronium bromide (Pavulon; Organon Teknika, Boxtel, the Netherlands) was intravenously injected for muscle relaxation.

A venous catheter (Truwave PX-600F; Baxter, Utrecht, the Netherlands) was introduced into the right jugular vein and advanced into the superior vena cava just above the right atrium. An arterial pressure catheter (Truwave PX-600F; Baxter) was introduced into the right carotid artery and advanced into the ascending aorta.

Midsternal thoracotomy was performed, and the thorax was opened. To prevent arrhythmia, lidocaine hydrochloride (AUV Coöperatie) was administered as a 50-mg bolus injection followed by a continuous 2 mg/min intravenous infusion. The pericardium was opened, and one or two diagonal branches of the left anterior descending coronary artery were ligated with a suture. The presence of occlusion was confirmed with development of myocardial cyanosis and electrocardiographic changes. After 30 minutes, the thorax was closed.

Immediately after extubation and on the 1st postoperative day, 3–10 mL of Prisantol (Intervet Nederland, Boxmeer, the Netherlands; 120 mg of phenylbutazone and 240 mg of isopropyl aminopyrine per milliliter [analgesic]) was administered subcutaneously. Antibiotics were administered daily: penicillin G procaine (Procpen [AUV Coöperatie], 300,000 IU administered intramuscularly) and gentamicin sulfate (Gentamicin 5% [AUV Coöperatie], 3 mL of a 5% solution, 50 mg of gentamicin administered intravenously). The animals recovered for 5 days.

During MR imaging, 5 days after coronary artery occlusion, the animals were anesthetized with the same medication as was administered for surgery. Midazolam hydrochloride (Dormicum; Roche Nederland, Mijdrecht, the Netherlands) was administered when necessary.

After the imaging procedure, the animals were sacrificed with a bolus injection of 20 mL of 7.5% potassium chloride (Kaliumchloride 7.5%; Fresenius `sHertogenbosch, the Netherlands; 1.429 g of potassium chloride) and 4 mg of pancuronium bromide. The hearts were excised, rinsed with saline solution, filled with 1% agar, and cooled to 4°C for 10 hours. The agar-rigid hearts were cut into 1-cm slices perpendicular to the interventricular groove and were stained with nitroblue tetrazolium chloride (Sigma Chemie, Zwijndrecht, the Netherlands) to demarcate the infarcted region. Nitroblue tetrazolium chloride stains normal myocardium dark blue or purple, while severely ischemic or infarcted tissue remains unstained (9).

MR Imaging
First-pass fast gradient-echo MR imaging and delayed spin-echo MR imaging of the myocardium were performed at 1.5 T (Gyroscan NT 15; Philips Medical Systems International, Best, the Netherlands). The animals were placed on their left side and examined with a 17-cm-diameter circular surface coil. For cardiac triggering of the MR imaging acquisition, the up slope of the aortic pressure was used, the signal for which was obtained from the catheter placed in the ascending aorta. Breath holds were achieved by turning off the respirator at end expiration. The systolic and diastolic blood pressures and pulse rate were monitored continuously during the study via the intraarterial catheter.

Baseline gradient-echo images were obtained in the coronal, sagittal, and transverse planes. The images were used to obtain oblique horizontal and vertical myocardial images in the long-axis plane. These images were used to obtain a double-oblique orientation to define the short-axis plane through the left ventricle.

Short-axis cine MR imaging was used to localize the section level with the largest area of infarction for first-pass perfusion imaging, with visual determination of the region with abnormal wall motion and wall thickening, markers of infarction (10). The following imaging parameters were used: 330-mm field of view; 128 x 128 matrix; 550/4.8 (repetition time msec [R-R aortic pressure up-slope interval]/echo time msec); 22–33-msec temporal resolution; echo-planar imaging factor of three k-y lines per echo-planar imaging, or EPI, segment; 30° flip angle; 7-mm section thickness; 11–14 phases per section; five to 10 section levels; and one breath hold per section level.

First-pass fast gradient-echo perfusion imaging was performed during P760 administration. The imaging parameters were as follows: 300–350-mm field of view, 113 x 128 to 128 x 128 matrix, 6.0–6.3/2.1, 15° flip angle, and 8-mm section thickness. During the breath hold, 100 images were obtained at one image per heartbeat, with a temporal resolution of approximately 550 msec. The contrast agent injection was initiated after acquisition of the fifth image to allow imaging of a steady-state baseline situation. A presaturation pulse was used to suppress the myocardial and ventricular cavity signals. The trigger delay was adjusted per animal to null the signal from the myocardium, and it was chosen to image in diastole.

First-pass imaging requires fast central venous bolus injection of the contrast agent to obtain adequate first-distribution imaging (11). The animals received P760 as a 3-mL compact bolus (0.0065 mmol/kg) followed by a 3-mL physiologic saline flush by manual injection within 2 seconds into the right atrium via the central venous catheter. In five pigs, the first-pass sequence was repeated 1 hour after P760 injection by using a 3-mL bolus of 0.05 mmol of the extracellular contrast agent gadoterate meglumine per kilogram, followed by a 3-mL physiologic saline flush.

T1-weighted spin-echo images were obtained before and after P760 administration by using the following imaging parameters: 330-mm field of view, 256 x 256 matrix, 550/30 (repetition time = aortic pressure up-slope interval), 7-mm section thickness, 0.7-mm intersection gap, five to eight sections acquired. The acquisition order of the k-y lines depended on the amount of respiratory motion to minimize artifacts due to respiration.

Image Analysis
The MR images were transferred to an UltraSPARC-1 workstation (Sun Microsystems, Mountain View, Calif). Image data were analyzed by using the MR Analytical Software System (MASS 3.0; R. J. Van der Geest, Leiden University Medical Center, Leiden, the Netherlands) (12). Photographed ventricular slices of excised nitroblue tetrazolium chloride–stained hearts, containing the maximal area of infarction, were digitized and transferred to the workstation.

A region of interest (ROI), as determined on the corresponding nitroblue tetrazolium chloride–stained slice, was drawn by one of the authors (L.J.M.K.) in the infarcted myocardium on gradient-echo and spin-echo images. The ROI for normal myocardium was drawn at a distance from the infarcted myocardium.

First-pass images.—The image analysis included the construction of the curves of signal intensity versus time for both ventricular cavities and the myocardium. Ventricular and myocardial contours were drawn on the initial image and were subsequently copied to all other images. To avoid artifactual measurements, the ROI within the infarcted myocardium was taken into account only when the ROI contained at least 15 pixels (in four pigs). First-pass maximum enhancement ratios of contours and ROIs were calculated as (maximum SI_FP)/SI_pre, where maximum SI_FP is the maximum signal intensity during the first pass and SI_pre is the precontrast signal intensity.

The enhancement ratio after the second pass at 40 seconds was measured in the right ventricle, the left ventricle, and the normal myocardium as SI₄₀/SI_pre, where SI₄₀ is the signal intensity at 40 seconds after contrast agent injection and SI_pre is the precontrast signal intensity.

Spin-echo images.—The difference between the signal intensities in the ROIs in the infarcted myocardium and those in the normal myocardium was calculated as the contrast ratio according to the following: (SI_infarct - SI_normal)/SI_normal, where SI_infarct is the signal intensity of the infarcted myocardium and SI_normal is the signal intensity of the normal myocardium. The enhancement percentage of the contrast ratio was measured as follows: [(contrast ratio after injection - contrast ratio before injection)/(contrast ratio before injection)] x 100.

The infarcted region revealed a "doughnut" pattern of enhancement in two animals. This doughnut pattern is characterized by an enhancing rim with a dark nonenhancing core. In these two animals, measurements were performed in the enhancing ring. In general, ROI measurements of infarcted myocardium contained at least 31 pixels.

Blood Samples
In two pigs, arterial blood samples were obtained before and at multiple intervals up to 1 hour after P760 and gadoterate meglumine injection to obtain plasma clearance curves. The gadolinium concentrations of P760 and gadoterate meglumine were quantified by means of atomic emission spectrometry by using direct-current plasma. Pharmacokinetic parameters were calculated according to a bicompartmental model, with adjustment to experimental points with the weighted least-squares method.

Statistical Analysis
The MR imaging values are expressed as the mean ± SEM. The paired two-tailed Student t test was used to determine the differences between enhancement of the right ventricle and that of the left ventricle and enhancement of the normal myocardium and that of the infarcted myocardium and the differences between P760 and gadoterate meglumine. P values less than .05 were considered to indicate a significant difference.

	RESULTS

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
MR imaging was successfully completed in seven animals; one animal was excluded from analysis due to inadequate and incomplete data acquisition. P760 bolus injections were hemodynamically well tolerated, as confirmed with electrocardiographic and blood pressure readings.

Fast Gradient-Echo Imaging
First-pass blood pool enhancement of the right ventricular cavity was significantly higher with P760 than with gadoterate meglumine (Table 1). Although a similar difference was observed for the left ventricular cavity during the first pass, it did not reach statistical significance. At 40 seconds after injection, blood pool enhancement for both ventricles was significantly higher with P760 than with gadoterate meglumine (Table 2).

View larger version (78K): [in this window] [in a new window]   Figure 1. Selected fast gradient-echo MR images (6.3/2.1, 15° flip angle) obtained in the myocardial short-axis view during the first pass of A-E, 0.0065 mmol/kg P760 and F-J, 0.05 mmol/kg gadoterate meglumine. A and F, Images obtained prior to injection. B and G, Images obtained at peak enhancement of the right ventricular blood pool (arrows). C and H, Images obtained at peak enhancement of the left ventricular blood pool (arrows). D and I, Images obtained at peak enhancement of the myocardium (arrows). E and J, Images obtained 40 seconds after contrast agent injection. Note that the evolution of enhancement for both contrast agents is similar, with more pronounced enhancement of the myocardium with gadoterate meglumine, which is related to a more pronounced extravascular diffusion. The blood pool signal intensity is higher in E than in J.

View larger version (13K): [in this window] [in a new window]   Figure 2a. First-pass perfusion curves in myocardial tissue (raw data) after injection of isoefficient doses of (a) P760 (0.0065 mmol/kg) and (b) gadoterate meglumine (0.05 mmol/kg). The signal intensity (SI) is in arbitrary units. The maximum first-pass signal intensity is higher in b than in a. In a, note the recirculation minimum at 10 seconds, after which the second pass occurs and the curve continues horizontally. In b, no recirculation minimum is seen, and the signal intensity decreases continuously. The curves are in accordance with the fast extravasation of gadoterate meglumine, whereas P760 remains in the blood pool during the imaging time window.

View larger version (13K): [in this window] [in a new window]   Figure 2b. First-pass perfusion curves in myocardial tissue (raw data) after injection of isoefficient doses of (a) P760 (0.0065 mmol/kg) and (b) gadoterate meglumine (0.05 mmol/kg). The signal intensity (SI) is in arbitrary units. The maximum first-pass signal intensity is higher in b than in a. In a, note the recirculation minimum at 10 seconds, after which the second pass occurs and the curve continues horizontally. In b, no recirculation minimum is seen, and the signal intensity decreases continuously. The curves are in accordance with the fast extravasation of gadoterate meglumine, whereas P760 remains in the blood pool during the imaging time window.

View larger version (159K): [in this window] [in a new window]   Figure 3a. (a) Short-axis pathologic nitroblue tetrazolium chloride-stained slice with myocardial infarction (arrow) in the left ventricular free wall. (b) Contours and ROIs drawn on a first-pass dynamic fast gradient-echo MR image (6.3/2.1, 15° flip angle) obtained in the myocardial short-axis view. The ROIs correspond to the left ventricular blood pool (ROI 1), infarction (ROI 2), and normal myocardium (ROI 3) on the nitroblue tetrazolium chloride-stained slice. (c) Corresponding P760 first-pass raw data curve of signal intensity (in arbitrary units) versus time shows the signal intensity in the left ventricular blood pool (solid line, corresponds to ROI 1), the infarcted myocardium (•, corresponds to ROI 2), and the normal myocardium (, corresponds to ROI 3). Note the clear increase in signal intensity during the first pass of P760 in the normal myocardium at 10-15 seconds, which is not seen in the infarcted myocardium.

View larger version (185K): [in this window] [in a new window]   Figure 3b. (a) Short-axis pathologic nitroblue tetrazolium chloride-stained slice with myocardial infarction (arrow) in the left ventricular free wall. (b) Contours and ROIs drawn on a first-pass dynamic fast gradient-echo MR image (6.3/2.1, 15° flip angle) obtained in the myocardial short-axis view. The ROIs correspond to the left ventricular blood pool (ROI 1), infarction (ROI 2), and normal myocardium (ROI 3) on the nitroblue tetrazolium chloride-stained slice. (c) Corresponding P760 first-pass raw data curve of signal intensity (in arbitrary units) versus time shows the signal intensity in the left ventricular blood pool (solid line, corresponds to ROI 1), the infarcted myocardium (•, corresponds to ROI 2), and the normal myocardium (, corresponds to ROI 3). Note the clear increase in signal intensity during the first pass of P760 in the normal myocardium at 10-15 seconds, which is not seen in the infarcted myocardium.

View larger version (16K): [in this window] [in a new window]   Figure 3c. (a) Short-axis pathologic nitroblue tetrazolium chloride-stained slice with myocardial infarction (arrow) in the left ventricular free wall. (b) Contours and ROIs drawn on a first-pass dynamic fast gradient-echo MR image (6.3/2.1, 15° flip angle) obtained in the myocardial short-axis view. The ROIs correspond to the left ventricular blood pool (ROI 1), infarction (ROI 2), and normal myocardium (ROI 3) on the nitroblue tetrazolium chloride-stained slice. (c) Corresponding P760 first-pass raw data curve of signal intensity (in arbitrary units) versus time shows the signal intensity in the left ventricular blood pool (solid line, corresponds to ROI 1), the infarcted myocardium (•, corresponds to ROI 2), and the normal myocardium (, corresponds to ROI 3). Note the clear increase in signal intensity during the first pass of P760 in the normal myocardium at 10-15 seconds, which is not seen in the infarcted myocardium.

View larger version (16K): [in this window] [in a new window]   Figure 4. Bar graph (bars ± SEM) demonstrates the mean contrast ratio between infarcted myocardium and normal myocardium on spin-echo images (550/30) before (pre) and after injection of 0.0065 mmol/kg P760 (in seven pigs). Within 5 minutes after P760 injection, the contrast ratio was improved, but this improvement was not statistically significant (ns) due to the variation within the group. The contrast ratio was significantly improved according to enhancement percentages of 129% at approximately 15 minutes (P = .002) and 124% at approximately 25 minutes (P = .003).

View larger version (146K): [in this window] [in a new window]   Figure 5a. (a) Short-axis pathologic nitroblue tetrazolium chloride-stained slice of infarcted myocardium (arrow). (b, c) T1-weighted spin-echo images (550/30) in the short-axis view show the corresponding level of myocardium (b) before and (c) 13 minutes after injection of P760. In b, the large infarction is not recognized. In c, the necrotic area is recognized as a dark core (arrow) surrounded by an enhancing rim.

View larger version (177K): [in this window] [in a new window]   Figure 5b. (a) Short-axis pathologic nitroblue tetrazolium chloride-stained slice of infarcted myocardium (arrow). (b, c) T1-weighted spin-echo images (550/30) in the short-axis view show the corresponding level of myocardium (b) before and (c) 13 minutes after injection of P760. In b, the large infarction is not recognized. In c, the necrotic area is recognized as a dark core (arrow) surrounded by an enhancing rim.

View larger version (186K): [in this window] [in a new window]   Figure 5c. (a) Short-axis pathologic nitroblue tetrazolium chloride-stained slice of infarcted myocardium (arrow). (b, c) T1-weighted spin-echo images (550/30) in the short-axis view show the corresponding level of myocardium (b) before and (c) 13 minutes after injection of P760. In b, the large infarction is not recognized. In c, the necrotic area is recognized as a dark core (arrow) surrounded by an enhancing rim.

View larger version (11K): [in this window] [in a new window]   Figure 6a. Semilogarithmic plots of plasma concentration versus time for (a) P760 and (b) gadoterate meglumine in two anesthetized pigs ( = pig 1, = pig 2). Note that the curve shapes in a and b are similar, in spite of the few data points soon after injection. The distribution into the extracellular compartment is mainly represented in the first phase after injection (fast decrease in gadolinium concentration [Gd conc] in micromoles per liter), whereas the excretion is mainly represented in the later (linear) phase (slower decrease in gadolinium concentration).

View larger version (11K): [in this window] [in a new window]   Figure 6b. Semilogarithmic plots of plasma concentration versus time for (a) P760 and (b) gadoterate meglumine in two anesthetized pigs ( = pig 1, = pig 2). Note that the curve shapes in a and b are similar, in spite of the few data points soon after injection. The distribution into the extracellular compartment is mainly represented in the first phase after injection (fast decrease in gadolinium concentration [Gd conc] in micromoles per liter), whereas the excretion is mainly represented in the later (linear) phase (slower decrease in gadolinium concentration).

	DISCUSSION

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

1. The high r1 of P760 causes pronounced blood pool enhancement with one-seventh of the normal dose of extracellular gadolinium compounds.

2. P760 has marked blood pool retention during the first pass, causing excellent blood pool enhancement and a blood pool–like curve for the myocardial first pass.

3. P760 is useful for identifying regional perfusion differences between normal myocardium and infarcted myocardium at first-pass gradient-echo imaging.

4. The late extracellular distribution improves the contrast between normal myocardium and infarcted myocardium at delayed spin-echo imaging.

5. P760 is eliminated quickly, which is comparable with an extracellular gadolinium compound.

P760 is classified as a slow-interstitial-diffusion or low-diffusion contrast agent. Its larger molecular size as compared with the sizes of conventional extracellular contrast agents prevents fast diffusion through the capillary membranes. Its enhancement during the first pass and during early circulation is therefore more like that of a blood pool agent. The distribution volume of the contrast agent is similar to the distribution volumes of conventional extracellular contrast agents and allows rapid renal clearance.

Fast Gradient-Echo First–Pass Imaging
There was a significantly higher first-pass maximum enhancement in the right ventricle than in the left ventricle for P760 that was not seen with gadoterate meglumine. The results suggest that there is less T2*-based signal intensity loss in the blood pool for P760 than for gadoterate meglumine, as the T2* effect is due to the local gadolinium concentration, which is lower for P760 than for gadoterate meglumine at an isoefficient dose.

In a comparison of the myocardial first-pass curves for P760 with those for gadoterate meglumine, there was a substantially higher normal myocardial enhancement for gadoterate meglumine than for P760. However, the higher enhancement for gadoterate meglumine can be explained by the fast extravasation (diffusion) into the interstitial space. Diffusion of any contrast agent from the blood pool into the myocardial interstitial space plays an important role in myocardial signal intensity measurements and hampers adequate quantification of myocardial perfusion (13). Intravascular contrast agents may simplify perfusion analysis (14). The blood pool–like enhancement of P760 during the first pass could be advantageous for quantitative evaluation of first-pass perfusion imaging. The peak intensity of passage of a contrast agent bolus is an efficient parameter for evaluating relative inhomogeneity of regional myocardial perfusion (3). In the present study, regional perfusion differences were identified between normal myocardium and infarcted myocardium at first-pass gradient-echo imaging by using P760.

The elimination half-life of currently experimental blood pool contrast agents is long (15,16). This limits repetitive injections during the same session. Repeat injections are needed to determine myocardial perfusion reserve in perfusion imaging under rest and stress conditions (17). The blood pool enhancement, in combination with the low dose and fast elimination rate that allow repeated injections, makes P760 a promising contrast agent for quantitative perfusion measurements.

Spin-Echo Imaging
Before P760 injection, there was little difference between the signal intensity of normal and that of infarcted myocardium. After P760 injection and diffusion of the contrast agent into the interstitial space, a clear enhancement of the infarcted area, confirmed pathologically, was shown at 15 and 25 minutes. Small infarctions were homogeneously enhanced, whereas large infarctions appeared as a dark core surrounded by an enhancing ring. These enhancement patterns are in agreement with those of extracellular contrast agents such as gadopentetate dimeglumine (2).

In conclusion, P760 is a newly designed extracellular contrast agent with improvements over conventional extracellular contrast agents for MR myocardial perfusion imaging. The strength of the product is based on the combination of high relaxivity and slow diffusion, which allow low-dose administration and cause a blood pool effect with improved enhancement. We believe that the slow-interstitial-diffusion contrast agent P760 warrants further investigation as a potential contrast agent for various MR applications.Practical application: P760 is a promising contrast agent for perfusion studies. Its blood pool retention with less background enhancement during a myocardial first pass is expected to be advantageous for quantitative perfusion measurements. The low dose and fast elimination allow repetitive injections as needed during stress testing. In addition, the combination of initial slow extravasation, high relaxivity, and low-dose administration is potentially valuable for MR imaging.

	Footnotes

 
Abbreviation: ROI = region of interest

Author contributions: Guarantor of integrity of entire study, L.J.M.K.; study concepts, L.J.M.K., A.d.R.; study design, L.J.M.K.; definition of intellectual content, A.d.R., L.J.M.K., J.D., R.J.v.d.G., S.B.; literature research, L.J.M.K., J.D.; experimental studies, L.J.M.K., J.D., S.B.; data acquisition, L.J.M.K., J.D.; data analysis, L.J.M.K., J.D., R.J.v.d.G., S.B.; statistical analysis, L.J.M.K.; manuscript preparation and editing, L.J.M.K.; manuscript review, J.D., A.d.R., S.B.

	References

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 

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