Published online before print June 26, 2006, 10.1148/radiol.2402051086
(Radiology 2006;240:419-426.)
© RSNA, 2006
MR Guidance of Targeted Injections into Border and Core of Scarred Myocardium in Pigs1
Maythem Saeed, DVM, PhD,
Alastair J. Martin, PhD,
Randall J. Lee, MD, PhD,
Oliver Weber, PhD,
Didier Revel, MD,
David Saloner, PhD and
Charles B. Higgins, MD
1 From the Departments of Radiology (M.S., A.J.M., O.W., D.R., D.S., C.B.H.) and Medicine and Cardiology (R.J.L.), University of California San Francisco, 513 Parnassus Ave, Room HSW 207 B, San Francisco, CA 94143-0628. Received June 28, 2005; revision requested August 23; revision received August 29; accepted September 22; final version accepted November 16.
Address correspondence to M.S. (e-mail: maythem.saeed{at}radiology.ucsf.edu).
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ABSTRACT
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Purpose: To use (a) dysprosium-based contrast agent (sprodiamide) to confirm the site of myocardial injection and (b) T1-enhancing magnetic resonance (MR) contrast media to mark the myocardial target and T2*-enhancing contrast media to demonstrate injection sites in the margins or core of infarction on delayed contrast-enhanced images.
Materials and Methods: Approval of the institutional committee on animal research was obtained. A phantom and six pigs subjected to chronic infarction (8 weeks) underwent MR-guided experiments. At inversion-recovery gradient-echo imaging, gadoterate meglumine (0.1 mmol/kg) was intravenously administered to delineate scar tissue. A catheter fitted with multiple receiver coils was used to visualize catheter navigation and injection sites. A steady-state free precession (balanced fast field-echo) sequence was used for MR fluoroscopy. A high-resolution multiphase balanced gradient-echo cine MR sequence was used after intramyocardial deposition of sprodiamide. The border and core of scarred myocardium were characterized histopathologically. The 95% confidence interval (CI) was used to demonstrate the range, extent of hyperenhanced and hypoenhanced regions after contrast media administration.
Results: In the phantom and in vivo, the actively guided catheter produced a high signal intensity at the terminal portion of the shaft and tip. Scarred myocardium was recognized as a bright region on gadoterate meglumine–enhanced images. Intramyocardial injection of sprodiamide caused local and persistent signal intensity loss, and the extent was volume dependent on balanced fast field-echo and T2-weighted turbo spin-echo images. At 5 minutes after administration of 0.2, 0.4, and 0.6 mL of sprodiamide, the 95% CIs of the extents of the hypoenhanced regions were 0.08%, 0.23%; 0.27%, 0.51%; and 0.46%, 0.70%, respectively, of left ventricular (LV) surface area (P < .05, paired t test). Failure of intramyocardial injection was confirmed by a brief signal loss of LV chamber blood.
Conclusion: Sprodiamide allows visualization of injection sites within enhanced infarction. A catheter with integrated receiver coils aided in effective catheter guidance and precise intramyocardial injection.
© RSNA, 2006
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INTRODUCTION
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The feasibility and effectiveness of intramyocardial cell therapy have been demonstrated in humans with direct epicardial injections (1,2). This approach, however, requires sternotomy, which is associated with high morbidity and mortality. Investigators have used an infarct-related artery as a means of delivering therapy (3,4), while others used intramyocardial access for drug delivery (5,6). Laham et al (7) found that after intracoronary administration, the retention of a solution of basic fibroblast growth factor in myocardium is very small (<1%). Intramyocardial delivery of therapeutic solutions provides higher local concentration; minimizes delivery of therapy to other pathologic regions, which can lead to acceleration of atherosclerosis (8); and minimizes potential systemic adverse effects such as hypotension (9). This route of administration of therapeutic solutions or cells is new and needs careful attention (10).
X-ray fluoroscopy (11,12) and electromechanical mapping (NOGA-STAR; Biosense-Webster, Waterloo, Belgium) (13,14) have been used in intramyocardial delivery. Electromechanical mapping allows detection of scar tissue as defined by reduced electric (<5 mV) and mechanical (local shorting <5%) activity (14). The major advantages of magnetic resonance (MR) guidance versus x-ray guidance are avoidance of radiation, reduction of the incidence of renal damage and allergic reaction induced by iodinated contrast media, and production of three-dimensional anatomic images and functional information (9,15) for procedural guidance.
Furthermore, the ability of MR imaging to help define acute and chronic myocardial infarctions makes it a suitable modality for targeting the myocardial site(s) for local administration of therapy (16,17). Several in vivo MR studies have demonstrated the use of noncellular solutions (15,18,19) or cells labeled with magnetite (iron particles) to mark the site of transcatheter delivery of solutions to the myocardium (20–23). Since positive enhancement is used to delineate infarcted myocardium (16,17), we propose that negative enhancement is the appropriate mechanism for monitoring the deposition of noncellular therapies.
In previous studies (20–23) investigators have used iron particles, which have T1 and T2 effects, to monitor the deposition of cellular therapies. Others (15,19) have used high-dose gadolinium chelates to mark the site of injection, which similarly will produce negative enhancement, but this approach results in background enhancement as the gadolinium chelates diffuse into the surrounding normal myocardium over the course of the intervention. As an alternative, MR susceptibility agents (reduce tissue signal intensity on T2- and T2*-weighted images) can be used to improve visualization of the injection site by creating a persistent signal intensity loss. Thus, the purposes of our study were to use (a) the susceptibility extracellular dysprosium-based contrast agent sprodiamide (Sprodiamide Injection; Nycomed, Oslo, Norway) to confirm the site of myocardial injection and (b) T1-enhancing MR contrast media to mark the myocardial target (infarcted myocardium) and T2*-enhancing MR contrast media to demonstrate the sites of injection in the margins or core of infarction on delayed contrast material–enhanced images.
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MATERIALS AND METHODS
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Dysprosium Chelates
MR contrast media act predominantly either on T1 relaxation (eg, gadoterate meglumine and gadopentetate dimeglumine), which results in higher signal intensity and positive enhancement on T1-weighted images, or on T2 relaxation (eg, dysprosium chelates and iron oxide particles), which results in lower signal intensity and negative enhancement on T1-weighted images (24). Dysprosium has five unpaired electron spins and an electron spin relaxation time that is in the range of 10–12–10–13 seconds. Dysprosium chelates shorten the apparent T2 relaxation time in their vicinity, darkening a T2-weighted image. Because sprodiamide has a short relaxation time, it is a poor T1 relaxation agent but acts as a bulk susceptibility contrast agent. Sprodiamide is a nonionic contrast agent with a plasma half-life in humans of 15–20 minutes. Sprodiamide alters signal intensity on MR images by substantially shortening T2 and T2*. Unlike gadolinium chelates, sprodiamide has a negligible T1 effect. This nonionic agent has a high safety margin in humans (25).
Animal Preparation
Care and maintenance of experimental animals were performed in accordance with the National Institutes of Health guidelines and with the rules of our committee on animal research. Six pigs weighing 20–25 kg were premedicated with ketamine (20 mg per kilogram of body weight; Parke-Davis, East Leigh, Hampshire, England), xylazine (2 mg/kg; Spectrum Chemicals and Laboratory Products, Gardera, Calif), and atropine (0.04 mg/kg; Abbott Laboratories, North Chicago, Ill). After intubation, the animals received a gas mixture of 1.5%–2.5% isoflurane (Abbott Laboratories) and 2–3 L/min of oxygen. The thorax was opened by using a median sternotomy. The left anterior descending coronary artery (n = 4) or obtuse marginal coronary artery (n = 2) was isolated and occluded with a snare for 2 hours to produce infarctions (target), followed by reperfusion by one author (M.S.). One of the two arteries was occluded to produce anterior or posterior infarctions and to test the potential of the active catheters to reach the desired subregions (core and proximal, distal, and lateral borders) of the target. Eight weeks after infarction, animals weighing 52–54 kg were reanesthetized as described earlier. Venous and arterial sheaths (4F; Bard-USCI, Billerrica, Mass) were introduced into the femoral vein and artery. Heart rate, blood pressure, and oxygen saturation were continuously measured by using a pressure transducer (Gould, Cleveland, Ohio) and oxygen sensor (In vivo Research, Orlando, Fla).
Active Endovascular Catheter
The endovascular catheter (n = 2) had a nitinol needle (Stiletto; Boston Scientific, Maple Grove, Minn) for puncturing the myocardial wall (22). The guiding catheter and the injection needle were adapted to serve as MR receiver coils in parallel with surface coils. The radiofrequency-sensitive components of the catheter included the catheter shaft and a small microcoil that was placed just proximal to the nitinol needle tip. The latter was to provide a high signal intensity on a separate transmission line that clearly indicated the location of the needle. The MR receiving coils and transmission lines were integrated into the lumen of the guiding catheter. The catheter was advanced across the aortic valve over a nitinol guidewire with MR fluoroscopic guidance. The catheter had two lumina: one for injection and/or blood sampling and one for pressure measurement. Once the nitinol needle was engaged in the myocardium, sprodiamide was delivered manually (M.S.) over the course of 15–20 seconds. Each animal received at least five injections (core and proximal, distal, and lateral borders of the target), and the distance between each injection site was approximately 2 cm, depending on the infarction size. A constant depth of 4 mm was chosen to prevent perforation of the scar tissue (15).
MR Imaging
Phantom model.—A 1.5-T MR imager (Philips Medical Systems, Best, Netherlands) was used in the phantom model and in vivo studies. The imaging parameters for the balanced steady-state free precession (balanced fast field-echo) sequence used for fluoroscopic purposes were 3.3/1.7 (repetition time msec/echo time msec), 50° flip angle, 360-mm field of view, 10-mm section thickness, 192 x 134 matrix, and acquisition time of 460 msec per image in continuous imaging. Receiver coils on the catheter shaft and needle were tested (A.J.M., O.W.) in a water bath in straight and deflected positions.
In vivo study.—A two-element phased array consisting of 20-cm-diameter circular surface coils was placed (A.J.M., O.W.) bilaterally against the animal's chest. After intravenous administration of gadoterate meglumine (0.1 mmol/kg; Guerbet Group, Paris, France), inversion-recovery gradient-echo (4.7/2.2/250–375 [repetition time msec/echo time msec/inversion time msec], 15° flip angle, 250-mm field of view, 10-mm section thickness, 240 x 120 matrix, multishot turbo field-echo sequence, shot factor of 25, shot delay of two R-R intervals, inversion delay set to null normal myocardium) and T1-weighted turbo spin-echo (one R-R interval/40, 5-mm section thickness, 200-cm field of view, 256 x 160 matrix, turbo spin-echo factor of 16, black blood double-inversion pulse, two signals acquired, acquisition time of approximately 9 seconds per section) images were acquired (15).
Inversion-recovery gradient-echo and T1-weighted turbo spin-echo (10-mm section thickness) images encompassing the entire left ventricle (LV) were acquired at baseline and 20 minutes after gadoterate meglumine administration to highlight the target (scarred myocardium). A steady-state free precession (balanced fast field-echo) sequence was used for catheter guidance. The external coils were used to define vascular anatomy and provide carotid and aortic road maps for use during catheter advancement. Once these planes were defined, the coils on the shaft of the catheter were turned on to better depict their orientation within the defined views.
Small volumes of 0.2, 0.4, and 0.6 mL of sprodiamide (0.5 mol/L) were injected (M.S.) into the core and proximal, distal, and lateral borders of the target (gadolinium-hyperenhanced scar tissue) to (a) demonstrate the site of delivery as a region of signal void, (b) ensure intramyocardial delivery, and (c) measure the extent of hypoenhanced region at 5 minutes after injection because the extent of the enhanced region expands as a function of time (19). Unlike extracellular gadolinium chelates, sprodiamide produces only T2* effects (signal loss). High-resolution multiphase balanced gradient-echo (steady-state) cine MR imaging (3.6/1.8, 70° flip angle, 270-mm field of view, 10-mm section thickness, 160 x 160 matrix, 16 heart phases) was performed to demonstrate the hypoenhanced zone during cardiac contraction. The period of advancement of nitinol guidewire and catheter and sprodiamide injections was almost 1 hour.
Histologic examination.—After imaging, the animals were sacrificed and the hearts were excised and sliced in planes that corresponded to the short-axis plane obtained at MR imaging. All slices were stained with 2% triphenyltetrazolium chloride (Spectrum Chemicals and Laboratory Products) at 37°C for 20 minutes to delineate scar tissue and were photographed. Findings of previous studies (15,18,19) showed close agreement between the region of scarred tissue at delayed contrast-enhanced MR imaging and that stained with triphenyltetrazolium chloride; thus, we did not repeat the procedure. Sliced hearts were fixed in formalin. Tissue samples from the regions of interest were obtained. The samples were obtained from the core (zone not stained by triphenyltetrazolium chloride) and border regions of the infarction. Tissue samples were stained with hematoxylin-eosin and Masson trichrome stains to define the scarred myocardium and to characterize blood vessels in each region (slides read by P. Ursell, MD, Department of Pathology, University of California San Francisco, oral communication, 2005).
Statistical Analysis
Regional signal intensity of remote and scarred myocardium after administration of gadoterate meglumine was determined, as well as the extent of the enhanced region in the entire heart. The 95% confidence interval was used to demonstrate the extent of hyperenhanced and hypoenhanced regions after administration of gadoterate meglumine and sprodiamide, respectively (M.S.). The extent of hypoenhanced regions after administration of different volumes of sprodiamide was also determined in the same animals 5 minutes after each injection and was compared by using analysis of variance. The paired t test was used to determine the significance of the difference in the heart rate, blood pressure, and oxygen tension before and after the intervention. The null hypothesis was rejected if P was less than .05.
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RESULTS
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Phantom Model
The endovascular catheter was tested in a phantom model prior to use in living animals. Figure 1 shows the active coils in the shaft and tip of the endovascular catheter in comparison to images obtained with external radiofrequency coils. The catheter-mounted coil elements produced a distinct area of high signal intensity, which allowed continuous visualization of the moving catheter in the water bath. Deflection of the catheter caused no change in the signal intensity for any active coil. The same acquisition parameters were applied afterward in vivo.
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Figure 1a: Long-axis MR images (4.0/2.0, 70° flip angle, 240-mm field of view, 160 x 160 matrix, 8-mm section thickness, 2 frames per second) acquired in water bath containing nitinol catheter and different active coil elements. (a) Only the external coil elements were active. (b) Only the catheter coil was active. (c) Only the catheter tip microcoil was active. (d) Field of view when all coil elements are contributing to the image. H = head, P = posterior.
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Figure 1b: Long-axis MR images (4.0/2.0, 70° flip angle, 240-mm field of view, 160 x 160 matrix, 8-mm section thickness, 2 frames per second) acquired in water bath containing nitinol catheter and different active coil elements. (a) Only the external coil elements were active. (b) Only the catheter coil was active. (c) Only the catheter tip microcoil was active. (d) Field of view when all coil elements are contributing to the image. H = head, P = posterior.
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Figure 1c: Long-axis MR images (4.0/2.0, 70° flip angle, 240-mm field of view, 160 x 160 matrix, 8-mm section thickness, 2 frames per second) acquired in water bath containing nitinol catheter and different active coil elements. (a) Only the external coil elements were active. (b) Only the catheter coil was active. (c) Only the catheter tip microcoil was active. (d) Field of view when all coil elements are contributing to the image. H = head, P = posterior.
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Figure 1d: Long-axis MR images (4.0/2.0, 70° flip angle, 240-mm field of view, 160 x 160 matrix, 8-mm section thickness, 2 frames per second) acquired in water bath containing nitinol catheter and different active coil elements. (a) Only the external coil elements were active. (b) Only the catheter coil was active. (c) Only the catheter tip microcoil was active. (d) Field of view when all coil elements are contributing to the image. H = head, P = posterior.
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In Vivo Study
Intravenous administration of 0.1 mmol/kg gadoterate meglumine highlighted scarred myocardium in the six pigs. The location of the scar tissue was dependent on the occluded coronary artery. The scarred myocardium (target) was depicted as a bright region on delayed contrast-enhanced inversion-recovery gradient-echo images. Intramyocardial injections with MR guidance were successful in five of six pigs. One pig died during catheterization because of ventricular fibrillation.
Endovascular catheter.—The advancement of the endovascular catheter in the aorta was monitored with MR fluoroscopy (10 images per second). The high signal intensity surrounding the catheter allowed visualization of the shaft and tip, while the external coils were primarily used to define the orientation of the catheter and illuminate the surrounding tissue (Fig 2). An oblique sagittal imaging plane that showed the descending and ascending aorta was used for LV catheterization at MR fluoroscopy.
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Figure 2: A–F, MR images demonstrate injection of sprodiamide into border and core of scarred myocardium. Delayed contrast-enhanced long-axis (A) and short-axis (D) views depict the scar (arrow). B, Injection catheter (arrow) is introduced into the LV and is manipulated with MR fluoroscopy until it is aimed at the desired target. The injection catheter contains two MR coils, one encompassing the catheter shaft and another depicting the tip of the catheter. C, Image resulting when external radiofrequency coils used in B are turned off and the catheter coil elements are used to create the MR image; area of high signal intensity (arrow) demarcates the catheter tip. Injection of sprodiamide can be monitored with MR fluoroscopy (arrow in E) and assessed after injection at cine MR imaging (arrow in F).
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Precise placement of the catheter tip within the LV chamber was made possible by rotating and deflecting the catheter (Fig 3). After proper positioning of the catheter tip into the region of interest (border or core of scar tissue), a transcatheter needle was advanced to penetrate the myocardium. The coil at the proximal tip of the needle facilitated precise localization prior to the delivery of sprodiamide to the desired sites in the targeted scar tissue (Figs 2, 4). There was no need to adjust the imaging parameters, except to change the imaging plane for optimal viewing.
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Figure 3a: Long-axis MR fluoroscopic images of the heart show tip of the active catheter (arrow) at (a) proximal portion, (b) core, and (c) distal portion of scarred thin wall of myocardium. Catheter illuminates the LV chamber and reaches different targets.
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Figure 3b: Long-axis MR fluoroscopic images of the heart show tip of the active catheter (arrow) at (a) proximal portion, (b) core, and (c) distal portion of scarred thin wall of myocardium. Catheter illuminates the LV chamber and reaches different targets.
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Figure 3c: Long-axis MR fluoroscopic images of the heart show tip of the active catheter (arrow) at (a) proximal portion, (b) core, and (c) distal portion of scarred thin wall of myocardium. Catheter illuminates the LV chamber and reaches different targets.
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Figure 4a: (a) Short- and (b–d) long-axis MR images of the heart. Scarred myocardium is seen as hyperenhanced region (arrow) after administration of 0.1 mmol/kg gadoterate meglumine. (c, d) MR images show the tip of the endovascular active catheter in the (c) distal and (d) proximal borders of the infarcted region. The sites of sprodiamide injections appear as small hypoenhanced regions (arrowhead).
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Figure 4b: (a) Short- and (b–d) long-axis MR images of the heart. Scarred myocardium is seen as hyperenhanced region (arrow) after administration of 0.1 mmol/kg gadoterate meglumine. (c, d) MR images show the tip of the endovascular active catheter in the (c) distal and (d) proximal borders of the infarcted region. The sites of sprodiamide injections appear as small hypoenhanced regions (arrowhead).
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Figure 4c: (a) Short- and (b–d) long-axis MR images of the heart. Scarred myocardium is seen as hyperenhanced region (arrow) after administration of 0.1 mmol/kg gadoterate meglumine. (c, d) MR images show the tip of the endovascular active catheter in the (c) distal and (d) proximal borders of the infarcted region. The sites of sprodiamide injections appear as small hypoenhanced regions (arrowhead).
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Figure 4d: (a) Short- and (b–d) long-axis MR images of the heart. Scarred myocardium is seen as hyperenhanced region (arrow) after administration of 0.1 mmol/kg gadoterate meglumine. (c, d) MR images show the tip of the endovascular active catheter in the (c) distal and (d) proximal borders of the infarcted region. The sites of sprodiamide injections appear as small hypoenhanced regions (arrowhead).
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Myocardial signal.—The delineation of scar tissue with gadoterate meglumine enabled precise delivery of sprodiamide to the core and borders of the target (Fig 2). There was signal loss around each side of the enhanced target, demonstrating the ability to "hit the target" (Fig 4). The extents of the enhanced regions were 8.77% and 15.43% (95% confidence interval) of the LV surface area at 20 minutes after systemic injection of 0.1 mmol/kg of gadoterate meglumine. The extents of the hypoenhanced regions were dependent on locally injected volumes. At 5 minutes after administration of 0.2, 0.4, and 0.6 mL of sprodiamide, the respective 95% confidence intervals of the extents of the hypoenhanced regions were 0.08%, 0.23%; 0.27%, 0.51%; and 0.46%, 0.70% of the LV surface area (P < .05, paired t test).
Figure 4 shows contrast medium injection at the distal (0.4 mL) and proximal (0.6 mL) border of the scarred myocardium. Injections were immediately visualized with the fluoroscopic balanced fast field-echo sequence as voids in the myocardial wall (Fig 5). Successful intramyocardial injection was confirmed by the persistent loss of myocardial signal intensity on T2-weighted turbo spin-echo images. Failure of intramyocardial injection was confirmed by a brief signal loss of the LV chamber blood. The signal void at the site of the delivery persisted for more than 15 minutes, which is in line with the plasma half-life of this agent. Typical duration to each intramyocardial injection was 10–15 minutes. Time recording began after the catheter and guidewire were introduced with MR guidance through a carotid sheath and ended when the first dose of sprodiamide was injected. Other intramyocardial injections took substantially less time (<10 minutes). The total time of the advancement of nitinol guidewire and catheter and sprodiamide injections (at least five injections) was almost 1 hour.
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Figure 5a: Oblique long-axis cine MR images show (a) endocardial and (b) transmural distribution of 0.6 mL of sprodiamide (arrows) in border region at posterior wall of the LV (in a case of obtuse coronary artery occlusion). At postmortem examination, there was no evidence of intramyocardial hemorrhage or any aortic valve or vascular damage.
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Figure 5b: Oblique long-axis cine MR images show (a) endocardial and (b) transmural distribution of 0.6 mL of sprodiamide (arrows) in border region at posterior wall of the LV (in a case of obtuse coronary artery occlusion). At postmortem examination, there was no evidence of intramyocardial hemorrhage or any aortic valve or vascular damage.
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Hemodynamic measurement.—Intramyocardial delivery of the T2* tissue marker was accomplished without deleterious hemodynamic effects in five pigs. Intramyocardial delivery of sprodiamide caused no significant changes in heart rate (97 beats per minute ± 5 before and 101 beats per minute ± 7 after injection), blood oxygen saturation (97% ± 3 before and 98% ± 2 after injection), or mean arterial blood pressure (78 mm Hg ± 5 before and 82 mm Hg ± 7 after injection). Similar findings have been reported in human volunteers (25).
Histochemical and Histopathologic Studies
At postmortem examination, there was no evidence of vascular perforation, aortic valve damage, or myocardial bleeding due to the advancement or manipulation of the endovascular catheter. Triphenyltetrazolium chloride staining confirmed the presence of myocardial infarction. Samples obtained from the core and border regions were stained with hematoxylin-eosin and Masson trichrome stains to characterize the structure of the border zone and to demonstrate the complete formation of scar tissue in the core. Histologic examination of the core of infarction revealed excessive collagen fibers and an abundance of remodeled conductive thick-wall blood vessels at 8 weeks after infarction. The invasion of scar tissue into normal myocardium was demonstrated by using Masson trichrome stain (Fig 6). Islands of viable myocytes were observed at the border of the scar tissue.
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Figure 6: Histopathologic specimen of core and border of scar tissue. Top: Transmural collagen fibers. (Hematoxylin-eosin stain; original magnification, x25.) Bottom: Islands of degenerated myocytes (arrows) at border of scarred myocardium of an 8-week-old myocardial infarction. (Masson trichrome stain; original magnification, x400.) Note invasion of scar tissue into viable myocardium at the border. Scar tissue is light red with hematoxylin-eosin stain and blue gray with Masson trichrome stain.
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DISCUSSION
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The combination of phantom, in vivo, and histologic examinations in our study provided valuable information. Imaging techniques sensitive to T1-, T2-, and ratio of T2/T2*-enhancing contrast media and a fluoroscopic steady-state free precession (balanced fast field-echo) sequence (active endovascular catheter) were successfully used in a single imaging session. Active tracking of endovascular devices with MR fluoroscopy provides a method for precise targeted myocardial delivery of soluble therapies doped with MR contrast media. Mounting of a microcoil at the tip of the catheter was crucial for targeting scarred myocardium.
Contrast-enhanced MR Imaging
MR sequences can be generated that primarily use either T1- or T2-enhancing contrast media, although strongly dephasing T2*-enhancing contrast agents tend to affect all imaging methods. Delayed contrast-enhanced T1-weighted MR images demonstrate regions of acute myocardial infarction and scar tissue as bright regions (16,17). This delayed enhancement persists for more than 2 hours after intracoronary injection of gadopentetate dimeglumine (26), which provides a sufficient window for several injections into the core and borders of the infarcted myocardium.
In our study, two MR imaging sequences (inversion-recovery gradient-echo and T2-weighted turbo spin-echo) and two MR contrast agents were used to define the scar tissue as bright region (T1 enhancing), while also depicting the site of injection as a dark zone (T2* enhancing). Moreover, images with an MR fluoroscopic sequence, which is based on a balanced fast field-echo acquisition and is known to exhibit contrast enhancement related to the ratio of T2 to T1, were also able to depict both scar tissue and injection sites, albeit with lower contrast enhancement.
A highly concentrated dose of a gadolinium chelate marks the injection site as a hypoenhanced zone (low-intensity focus) at the border of the hyperenhanced scar. After a few minutes, the gadolinium chelate becomes less concentrated, so the effect of low signal intensity is lost and the injection site becomes bright (15,19), which results in blending of the target. However sprodiamide produces a prolonged myocardial signal loss (24), allowing several injections at different sites of the bright scar tissue. The washout of sprodiamide from myocardium is similar to that of other extracellular gadolinium chelates but differs from that of iron particles, which stay for weeks after injection (20–23). This relatively rapid washout of dysprosium may reduce the death of injected cells, which is often seen in iron-labeled cells.
Active Catheter Tracking
Catheter navigation is routinely performed with x-ray guidance; however, the site and extent of the infarcted myocardial region cannot be defined on two-dimensional x-ray fluoroscopic images (15). This new active tracking method is better than passive catheter tracking used in our previous study (15). Passive catheter tracking is challenging because it can be difficult to ensure that the device is within the imaging section; also, thicker sections are associated with inferior image contrast and resolution (15,27). Placement of receiver coils on the endovascular catheter improves signal detection near the tip of the catheter, which makes the localization and delineation of the device much easier (23). One of the advantages of using resonance markers for localization purposes is their strong positive image contrast (high signal intensity of the distal catheter and tip) (28). The use of MR fluoroscopy to guide the delivery of local noncellular solutions (15,19) and cells (20–23) has been previously documented. Electromechanical mapping technology (13,14) is an alternative technique for guiding endovascular catheters and intramyocardial injections. Electromechanical mapping uses electromagnetic field sensors to combine and integrate real-time information from percutaneous intracardiac electrograms acquired at multiple endocardial locations to distinguish between normal and infarcted myocardium. Although electromechanical mapping has been used in evaluating the effect of angiogenic factors in patients (29), safety concerns led to its recent withdrawal from the market.
Tissue samples obtained from the core and border regions of the infarction indicated that there was no evidence of the presence of viable myocytes in the core of the infarction but that there was an abundance of remodeled blood vessels. In contrast, it was found that degenerative myocytes were present at the border region, which indicates either regional ischemia or continuous strain. These findings suggest that the core and border regions may need different local therapies, vascular endothelial growth factors, genes, and stem cells.
The study had limitations. The death of one animal out of six during the intervention shows the procedure is still risky. The other limiting factor of this approach is the safety of the active catheter in the MR environment, which has been previously addressed (30,31). The probability of catheter heating as a potential hazard was not assessed in our study. The future growth of endovascular and intramyocardial MR-guided procedures depends on the safety and continued advancement of MR-compatible delivery devices.
Practical application: The use of real-time fluoroscopy to guide the delivery of local therapies (eg, as drugs, vascular growth hormones, genes, stem cells) is feasible. Active catheters can be more easily visualized and navigated with MR guidance than passive catheters (15) and proved to be capable of reaching selected targets in the scarred myocardium. Doping of therapeutic drugs with the nonionic extracellular MR contrast medium sprodiamide is a potential method for monitoring the distribution of soluble drugs in myocardium. Dysprosium chelate is useful in ensuring intramyocardial delivery of local therapies (such as genes or stem cells) and in providing delineation of the injection site, without the risk of iron overload derived from nonviable iron-labeled stem cells.
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ADVANCES IN KNOWLEDGE
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- Doping of a therapeutic solution with nonionic extracellular MR contrast medium is a method for monitoring the distribution of soluble drugs in infarcted myocardium.
- Endovascular catheter navigation can be better visualized with MR fluoroscopic guidance.
- A catheter with integrated receiver coils aided in ensuring intramyocardial injection.
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FOOTNOTES
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Abbreviations: LV = left ventricle
A.J.M. was an employee of Philips Medical System, Best, the Netherlands, at the time the manuscript was submitted.
Author contributions: Guarantor of integrity of entire study, M.S.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, M.S.; experimental studies, M.S., A.J.M., R.J.L., O.W., D.R., D.S.; statistical analysis, M.S.; and manuscript editing, all authors
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References
|
|---|
- Kajstura J, Leri A, Finato N, et al. Myocyte proliferation in end-stage cardiac failure in humans. Proc Natl Acad Sci U S A 1998;95:8801–8805.[Abstract/Free Full Text]
- Menasche P, Hagege AA, Scorsin M, et al. Myoblast transplantation for heart failure. Lancet 2001;357:279–280.[CrossRef][Medline]
- Schachinger V, Assmus B, Britten MB, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final 1-year results of the TOPCARE-AMI trial. J Am Coll Cardiol 2004;44:1690–1699.[Abstract/Free Full Text]
- Britten MB, Abolmaali ND, Assmus B, et al. Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI). Circulation 2003;108:2212–2218.[Abstract/Free Full Text]
- Fuchs S, Satler LF, Kornowski R, et al. Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study. J Am Coll Cardiol 2003;41:1721–1724.[Abstract/Free Full Text]
- Laham RJ, Rezaee M, Post M, et al. Intramyocardial delivery of fibroblast growth factor-2 induces neovascularization in a porcine model of chronic myocardial ischemia. J Pharmacol Exp Ther 2000;292:795–802.[Abstract/Free Full Text]
- Laham RJ, Rezaee M, Post M, et al. Intracoronary and intravenous administration of basic fibroblast growth factor: myocardial and tissue distribution. Drug Metab Dispos 1999;27:821–826.[Abstract/Free Full Text]
- Inoue M, Ito H, Ueda M, et al. Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: possible pathophysiological significance of VEGF in progression of atherosclerosis. Circulation 1998;98:2108–2116.[Abstract/Free Full Text]
- Saeed M, Saloner D, Weber O, et al. MRI in guiding and assessing intramyocardial therapy. Eur Radiol 2005;15:851–863.[CrossRef][Medline]
- Lee RJ, Springer ML, Blanco-Bose, Shaw R, Ursell P, Blau HM. VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation 2000;102:898–901.[Abstract/Free Full Text]
- Rezaee M, Yeung AC, Altman P, et al. Evaluation of the percutaneous intramyocardial injection for local myocardial treatment. Catheter Cardiovasc Interv 2001;53:271–276.[CrossRef][Medline]
- Sanborn TA, Hackett NR, Lee LY, et al. Percutaneous endocardial transfer and expression of genes to the myocardium utilizing fluoroscopic guidance. Catheter Cardiovasc Interv 2001;52:260–266.[CrossRef][Medline]
- Fuchs S, Baffour R, Zhou YF, et al. Transendocardial delivery of autologous bone marrow enhances collateral perfusion and regional function in pigs with chronic experimental myocardial ischemia. J Am Coll Cardiol 2001;37:1726–1732.[Abstract/Free Full Text]
- Kornowski R, Hong M, Gepstein L, et al. Preliminary animal and clinical experiences using an electromechanical endocardial mapping procedure to distinguish infarcted from healthy myocardium. Circulation 1998;98:1116–1124.[Abstract/Free Full Text]
- Saeed M, Lee RJ, Martin A, et al. Transendocardial delivery of extracellular myocardial markers by using combination x-ray/MR fluoroscopic guidance: feasibility study in dogs. Radiology 2004;231(3):689–696.[Abstract/Free Full Text]
- Kim RJ, Fieno DS, Parrish TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation 1999;100:1992–2002.[Abstract/Free Full Text]
- Saeed M, Wendland MF, Watzinger N, et al. MR contrast media for myocardial viability, microvascular integrity and perfusion. Eur J Radiol 2000;34:179–195.[CrossRef][Medline]
- Krombach GA, Baireuther R, Higgins CB, Saeed M. Distribution of intramyocardially injected extracellular MR contrast medium: effects of concentration and volume. Eur Radiol 2004;14:334–340.[CrossRef][Medline]
- Krombach GA, Pfeffer JG, Kinzel S, Katoh M, Guenther RW, Buecker A. MR-guided percutaneous intramyocardial injection with an MR-compatible catheter: feasibility and changes in T1 values after injection of extracellular contrast medium in pigs. Radiology 2005;235:487–494.[Abstract/Free Full Text]
- Kraitchman DL, Heldman AW, Atalar E, et al. In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infarction. Circulation 2003;107:2290–2293.[Abstract/Free Full Text]
- Hill JM, Dick AJ, Raman VK, et al. Serial cardiac magnetic resonance imaging of injected mesenchymal stem cells. Circulation 2003;108:1009–1014.[Abstract/Free Full Text]
- Dick AJ, Guttman MA, Raman VK, et al. Magnetic resonance fluoroscopy allows targeted delivery of mesenchymal stem cells to infarct borders in swine. Circulation 2003;108:2899–2904.[Abstract/Free Full Text]
- Karmarkar PV, Kraitchman DL, Izbudak I, et al. MR-trackable intramyocardial injection catheter. Magn Reson Med 2004;51:1163–1172.[CrossRef][Medline]
- Saeed M, Wendland MF, Yu KK, Higgins CB. The utility of optimal dose of dysprosium-DTPA-BMA in the delineation of acute myocardial infarction. J Am Coll Cardiol 1992;20:1634–1641.[Abstract]
- Sakuma H, O'Sullivan M, Lucas J, et al. Effect of magnetic susceptibility contrast medium on myocardial signal intensity with fast gradient-recalled echo and spin-echo MR imaging: initial experience in humans. Radiology 1994;190:161–166.[Abstract/Free Full Text]
- Ni Y, Pislaru C, Bosmans H, et al. Intracoronary delivery of Gd-DTPA and Gadophrin-2 for determination of myocardial viability with MR imaging. Eur Radiol 2001;11:876–883.[CrossRef][Medline]
- Martin AJ, Weber OM, Saeed M, Roberts TP. Steady-state imaging for visualization of endovascular interventions. Magn Reson Med 2003;50:434–438.[CrossRef][Medline]
- Lewin JS, Duerk JL, Jain VR, et al. Needle localization in MR-guided biopsy and aspiration: effect of field strength, sequence design and magnetic field orientation. AJR Am J Roentgenol 1996;166:1337–1345.[Abstract/Free Full Text]
- Vale PR, Losordo DW, Milliken CE, et al. Left ventricular electromechanical mapping to ass efficacy of phVEGF(165) gene transfer for therapeutic angiogenesis in chronic myocardial ischemia. Circulation 2000;102:965–974.[Abstract/Free Full Text]
- Nitz WR, Oppelt A, Renz W, Manke C, Lenhart M, Link J. On the heating of linear conductive structures as guidewires and catheters in interventional MRI. J Magn Reson Imaging 2001;13:105–114.[CrossRef][Medline]
- Yeung CJ, Susil RC, Atalar E. RF heating due to conductive wires during MRI depends on the phase distribution of the transmit field. Magn Reson Med 2002;48:1096–1098.[CrossRef][Medline]
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ABSTRACT
INTRODUCTION
