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DOI: 10.1148/radiol.2352031760
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(Radiology 2005;235:487-494.)
© RSNA, 2005

Experimental Studies

MR-guided Percutaneous Intramyocardial Injection with an MR-compatible Catheter: Feasibility and Changes in T1 Values after Injection of Extracellular Contrast Medium in Pigs1

Gabriele A. Krombach, MD, Joachim G. Pfeffer, Sylvia Kinzel, DVM, Markus Katoh, MD, Rolf W. Günther, MD and Arno Buecker, MD

1 From the Departments of Diagnostic Radiology (G.A.K., J.G.P., M.K., R.W.G., A.B.) and Experimental Veterinary Medicine (S.K.), University Hospital of the University of Technology, Pauwelstrasse 30, 52057 Aachen, Germany. Received October 31, 2003; revision requested January 26, 2004; final revision received July 9; accepted August 17. Address correspondence to G.A.K. (e-mail: krombach@rad.rwth-aachen.de)


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To assess the feasibility of percutaneous magnetic resonance (MR)-guided intramyocardial injection of gadodiamide by using real-time imaging and to quantify T1 values and the size of the enhanced region for different concentrations of contrast agent for 30 minutes after injection.

MATERIALS AND METHODS: Animal care committee approval was obtained. A catheter with a needle tip was advanced into the left ventricle in seven pigs by using real-time imaging with radial steady-state free precession. After intramyocardial injection of 2 mL of solution at concentrations of 0.05 or 0.10 mmol/mL gadodiamide, local changes in T1 values and size of the contrast material–enhanced region were sequentially measured at 3, 15, and 30 minutes after injection by using the Look-Locker sequence. Two-tailed paired Student t tests were used for statistical analysis.

RESULTS: Catheter guidance and visualization of contrast agent distribution were feasible in all animals. Regional changes in T1 values were significantly different for different contrast agent concentrations (for 0.05 mmol/mL, 456 msec ± 5 [± standard error of the mean]; for 0.10 mmol/mL, 228 msec ± 4; P < .001) measured 3 minutes after injection. T1 values increased significantly (P < .05) to 720 msec ± 7 for 0.05 mmol/mL gadodiamide and 445 msec ± 6 for 0.10 mmol/mL gadodiamide 30 minutes after injection but remained significantly lower than those of remote myocardium (879 msec ± 8). The size of the contrast-enhanced region increased from 13 mm2 ± 2 at 3 minutes to 30 mm2 ± 3 at 30 minutes (P < .05).

CONCLUSION: Catheter MR-guided percutaneous intramyocardial injection is feasible; after intramyocardial injection of gadodiamide at concentrations of 0.05 and 0.10 mmol/mL, T1 values decreased over the observation time.

© RSNA, 2005


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Molecular intervention targeted directly to the myocardium to initialize angiogenesis in coronary heart disease has been suggested and introduced as an adjuvant revascularization technique or systemic pharmacologic treatment (1–6). Results of phase I and II trials in patients have already demonstrated that administration of vascular endothelial growth factor and fibroblast growth factor can efficiently improve myocardial blood flow (7–10). Substrates were initially administered systemically (11) and later were administered directly into the coronary arteries or into the pericardium (12). However, results of clinical studies have demonstrated that, with these routes, effective concentration of therapeutic substrates could not be achieved (13,14). Surprisingly, after intracoronary delivery less than 1% of the substrate was retained in the myocardium (15). As a consequence, intramyocardial delivery of substrates has been proposed (16) and has been performed either during bypass surgery or by means of a minithoracotomy in patients (4,9).

Intramyocardial injection has been attempted with catheter-based approaches to provide a less-invasive technique. In the majority of studies, fluoroscopic guidance was used (17,18). The drawback of this technique is the inability to directly delineate the myocardium and the left ventricular target areas. The lack of direct visualization of the myocardium bears the risk of insufficient distribution of the injected substrate within the target areas. This insufficient distribution, however, may delay treatment for several months.

Magnetic resonance (MR) imaging is an established technique for the accurate delineation of the extent of ischemically injured myocardium. Recent advances in interventional MR imaging, such as the introduction of steady-state free precession imaging combined with radial acquisition of k-space lines (19,20), may close the gaps between delineation of ischemically injured myocardium, catheter-mediated intramyocardial injection of substrates, and monitoring of primary distribution of substrates within the myocardium. The feasibility of MR-guided injection into the myocardium by using a prototype catheter for active tracking (ie, tracking based on additional hardware mounted on the catheter, such as a resonance circuit) and a custom reconstruction software solution has recently been demonstrated (21,22). However, to our knowledge there is no study in which passive catheter tracking and commercially available real-time MR guidance for intramyocardial injection have been used.

Although distribution of intravenously administered gadopentetate dimeglumine in the heart has been extensively evaluated, little is known about the obtainable changes in T1 values after intramyocardial injection of different concentrations of extracellular contrast media. In a previous study, concentrations of gadodiamide suited for intramyocardial injection after thoracotomy were assessed (23). Accordingly, the purposes of the current study were to assess the feasibility of percutaneous MR-guided intramyocardial injection of gadodiamide by using real-time imaging and to quantify T1 values and the size of the contrast material–enhanced region for different concentrations of the contrast agent for 30 minutes after injection.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals
Seven domestic female pigs were included in the current study. The local animal care committee approved this trial. Body weight of the animals was between 39 and 60 kg (mean, 46 kg). All interventions were performed with general anesthesia that was induced with intramuscularly applied atropine (0.5 mL per 10 kg body weight; WDT, Garbsen, Germany), azaperone (2 mL per 10 kg body weight; Janssen-Cilay, Neuss, Germany), and ketamine (1 mL per 10 kg body weight; Ceva, Duesseldorf, Germany) and that was maintained with intravenous pentobarbital sodium (Merial, Hallbergmoos, Germany), as needed. The pigs were intubated and mechanically ventilated. Carotid artery sheaths (9 F) were placed in all animals (S.K.). Mean heart rate was 100 beats per minute (range, 95–110 beats per minute).

Experimental Protocol
All experiments were performed by using an interventional 1.5-T MR system (ACS NT; Philips, Best, the Netherlands) with a gradient strength of 23 mT/m and a maximal rise time of 200 µsec (Power Trak 6000; Philips). The imager is a closed-bore system with a length of 1.61 m and a width of 60 cm at the isocenter. Real-time MR images are displayed on a liquid crystal display, or LCD, screen next to the imager with a delay of 100 msec after image reconstruction. The geometric dimensions and the near real-time display allow for catheter manipulation at the introducer sheath while the region of interest (ROI) is positioned at the isocenter of the system. MR sequence settings loaded from the console of the imager can be changed during operation from within the radiofrequency-shielded room by using the LCD display at the imager and a remote control (Philips).

In the first animal, we used an Elgiloy needle for intramyocardial injections. In this animal, the artifact arising from the elgiloy needle was visible over the whole length of the needle. Because of this artifact, the surrounding anatomic structures were slightly blurred on radial real-time MR images. It was difficult to detect the actual needle tip and to differentiate it from the needle shaft under this condition. As a consequence, we did not use this catheter in the remaining animals. For the remaining six animals, we used a catheter with a plastic shaft built by fixating a 6-mm-long stainless steel needle (7 F) to a 7-F polyethylene catheter (Cook, Bjaeverskov, Denmark) (J.G.P.). The needle tip protruded 3 mm out of the catheter tip. The catheter was introduced and advanced via the aorta into the left ventricle. The catheter position was continuously monitored by using a real-time steady-state free precession, also known as balanced fast field-echo, sequence and radial k-space sampling without breath hold or cardiac triggering.

MR imaging parameters were as follows: repetition time msec/echo time msec, 2.5/1.25 (because of a rounding error, the imager displayed an echo time of 1.2 msec with a repetition time of 2.5 msec; however, the correct echo time was 1.25 msec); flip angle, 45°; field of view, 320 mm2; and a matrix of 128 x 128 reconstructed to 256 x 256 by using zero filling. One image was reconstructed from 80 radial k-space lines (24,25). Reconstruction of real-time images was performed by using the sliding-window reconstruction technique (24). For image reconstruction, the "oldest" data of the k-space are replaced by newly acquired k-space lines (here, 20 radial k-space lines), while the rest of the data are kept (24,26). The temporal resolution was 15 frames per second. Since Fourier analysis is not applicable with this approach, a dedicated back-projector composed of a computer with specially developed software (Philips Research Laboratories, Hamburg, Germany) was employed for image reconstruction (25).

MR images were displayed in real time on the liquid crystal display screen next to the imager to provide control of catheter manipulations. Imaging parameters such as section position, imaging plane, flip angle, section thickness, and repetition time could be changed interactively. However, during the intervention we changed only the image position and section plane, in order to follow the catheter.

After the needle-tipped catheter and the introducer sheath were advanced into the left ventricle, the catheter was advanced while the introducer sheath was not moved. From this point on, the tip of the catheter was no longer shielded. The needle was directed to the previously chosen target area (A.B., G.A.K.). Target areas were chosen prior to injection to test whether it was possible to direct the catheter to these areas. As soon as the catheter left the plane of the imaging section, manipulation of the catheter was stopped and the section position was adapted to the position of the catheter (G.A.K., A.B., M.K.). Most of the time, this was possible by keeping the angulations of the section plane but moving the section position. However, when the angle of the catheter changed, first the image plane was changed to an orientation perpendicular to the catheter. In a second step, the section plane was adapted to the course of the catheter. Thus, the catheter could be safely directed to the wall of the left ventricle and inserted into the myocardium (A.B., G.A.K.). Gadodiamide (Omniscan; Nycomed, Cork, Ireland) was diluted with NaCl solution to obtain isotonic concentrations of 0.05 mmol/mL (10% gadodiamide solution) and 0.10 mmol/mL (20% gadodiamide solution). These concentrations were chosen according to the experience derived from a previous experiment, in which different concentrations of gadodiamide were injected into beating hearts, animals were killed 5 minutes after injections, and the excised hearts were imaged (23). In the current study, in each animal, two to six injections of the different concentrations of gadodiamide were performed, remote from each other. The number of injections performed in each animal is listed in Table 1. After each injection, the catheter was removed and reintroduced for subsequent injections.


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  		TABLE 1. Number of Injections of Gadodiamide Solution per Animal

 
Anatomic Analysis
After all MR acquisitions were completed, including estimation of the T1 values, the animals were sacrificed. The pericardium was opened to check for intrapericardial bleeding (G.A.K., A.B., S.K.). The heart was removed, and the left ventricle was sliced into 8-mm-thick slabs along the short-axis plane. Slabs were visually examined for intramyocardial hematoma (G.A.K., A.B., S.K.). Tissue slabs were not exactly registered to the imaging sections. Instead, basal tissue slabs were considered to correspond to basal short-axis MR images, while apical tissue slabs were considered to correspond to apical short-axis MR images.

Measurement of T1 Values and Image Analysis
After injections, T1 values were obtained. For this purpose, a sequence introduced by Look and Locker was used (27). This sequence has recently been used for quantification of T1 values after administration of different contrast media (28–30). The Look-Locker sequence was performed with the following parameters: 3000/3.5; field of view, 320 mm; flip angle, 10°; echo-planar imaging factor of three; and a 128 x 128 matrix, resulting in an isotropic 2.5-mm in-plane resolution. Signals were not averaged. After an initial 180° pulse triggered to the R wave, 100 images were acquired with an interval of 30 msec between consecutive images. The interval of 30 msec allowed for a sufficient timely resolution at a reasonable data rate (28). This means we chose the interval of 30 msec to be able to measure the zero crossing at the injection site more exactly than would have been possible with longer time intervals, such as, for example, 50 msec. The acquisition time for one set of single-section images was 2.56 minutes. This time slightly exceeds the time calculated from the pulse sequence diagram (130 seconds) because of preparation of the imager and reconstruction of images. For injections of 2 mL of gadodiamide solution, we deemed the spatial resolution of 2.5 mm2 of the Look-Locker sequence to be sufficient for the delineation of possible signal intensity changes at the injection sites; that is, we expected the volume of 2 mL to be high enough to cause changes in the regional T1 values, which could be assessed with the previously described Look-Locker sequence.

To obtain reliable values for a given T1 value, a time period in the range of three times the expected T1 value has to be covered after the inversion pulse. Since T1 is around 800 msec for the normal myocardium, we covered 3000 msec with the Look-Locker sequence. T1 values were calculated from the Lock-Locker data by using a curve fit model (27–29) for ROIs at the following locations: (a) myocardium injection site (size of ROIs, 75–114 mm2), (b) myocardium remote from the injection site (size of ROIs, 40–200 mm2), (c) blood pool in the center of the left and in the center of the right ventricle (size of ROIs, 137–225 mm2), (d) skeletal muscle of the autochthonous back muscles of the left side (size of ROIs, 712–787 mm2), and (e) subcutaneous fat of the back on the left side (size of ROIs, 23–56 mm2).

The ROI was manually drawn on one image and was copied to the remaining images and adjusted to correct for cardiac motion. The obtained signal intensity values were fitted to a T1 relaxation curve by using a least-squares method, thus compensating for the saturation arising from radiofrequency excitation (28). The Look-Locker sequence for measurement of T1 values was performed immediately and at 15 and 30 minutes after the injections. The window of 30 minutes was used because within this time, subsequent injections during an intervention should be feasible. The size of the contrast-enhanced region in a single section was measured at the same points in time to evaluate changes in the size of the contrast-enhanced region (G.A.K., 5 years of experience in cardiac MR imaging). The borders between nonenhanced and contrast-enhanced myocardium were clearly visualized, which allowed for outlining of the regions.

In addition, the ratio of the signal intensity at the injection site to the signal intensity of remote myocardium was assessed from the real-time images obtained after injection to determine the contrast between the regions (G.A.K.). For this purpose, ROIs were drawn at the injection site (size of ROI, 70–120 mm2) and in remote myocardium (septum of the left ventricle in the same section; size of ROI, 30–200 mm2). In addition, contrast-to-noise ratio was calculated from the real-time images. For this purpose, the background noise was additionally measured in an image region in front of the chest wall (air; size of ROI, 188–1242 mm2). The contrast-to-noise ratio was calculated by obtaining the difference between the signal-to-noise ratio of the myocardium (signal intensity value of remote myocardium divided by that of background signal intensity) and signal-to-noise ratio of the injection site.

Statistical Analysis
All values are presented as mean ± standard error of the mean. Statistical analysis was performed by using commercially available statistical software (JMP; SAS Institute, Cary, NC). Differences among mean T1 values in the injected and noninjected regions and the sizes of contrast-enhanced regions were determined within the same hearts by using two-tailed paired Student t tests. Unpaired t tests were used for comparison between animals. If this analysis showed an overall P value of less than .05, the null hypothesis was rejected.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
In all animals, intramyocardial injections were successfully performed with no side effects, such as changes in heart rate, left ventricular arrhythmia, or cardiac arrest.

The catheter used in this study was clearly visible on real-time radial steady-state free precession images as a dark structure against the bright blood pool (Fig 1). There was a small artifact arising from the needle tip (Fig 1). These imaging features facilitated guidance of the catheter into the left ventricle, confident evaluation of the position of the needle tip, and insertion of the needle into the myocardium. Thus, the catheter could be directed into the regions selected beforehand for injection in all cases. The catheter could be traced during the intervention by interactively changing the imaging plane during imaging, as soon as the catheter left the imaging plane. Anatomic structures in the vicinity of the catheter were not obscured by the artifact associated with the catheter needle tip.



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  		Figure 1. Radial steady-state free precession MR images (2.5/1.2; flip angle, 45°; temporal resolution, 66 msec per image) obtained with a long-axis view of the left ventricle. Top row: Catheter is clearly visible as a dark structure (arrow) with a small artifact arising from its tip. Bottom row: The catheter was advanced into the left ventricle (left), while still inside the introducer sheath, and then inserted into the myocardium (arrow). During injection of gadodiamide solution (right), there was a growing area of high signal intensity (arrow) within the myocardium surrounding the needle tip.

 
After maneuvering the introducer sheath with the needle catheter into the left ventricle, the needle was inserted into the previously chosen target segment (Fig 1). During injection of the contrast medium, a growing bright region extending from the needle tip into the surrounding myocardium was visible on radial steady-state free precession images (Fig 1). Evidence of local complications, such as intramyocardial hematoma, were not detected on real-time images in any animal. However, in one animal, perforation of the myocardium occurred. This resulted in bleeding into the pericardium and a small hemorrhagic pericardial effusion. This hemorrhagic effusion became visible on the real-time images, as well as on the Look-Locker images, shortly after perforation. These results correlated with those of postmortem inspection of the pericardium and myocardium.

Intramyocardial delivery of gadodiamide caused a significant increase in regional signal intensity compared with remote myocardium on real-time radial MR images (Fig 1). Signal intensity ratio (regional signal intensity measured at the injection site divided by signal intensity of remote myocardium) was significantly higher after injection of a concentration of 0.10 mmol/mL (signal intensity ratio, 3.05 ± 0.07), compared with a concentration of 0.05 mmol/mL (signal intensity ratio, 2.45 ± 0.05; P < .05). These changes in signal intensity ratio can be explained by means of changes in T1 values obtained after injection of different concentrations of gadodiamide. The contrast-to-noise ratio was 3.9 ± 0.96 for 0.05 mmol/mL and 13.77 ± 0.76 for 0.10 mmol/mL.

Table 2 summarizes T1 values calculated on the basis of the Look-Locker images from remote myocardium, injection sites after injection of different concentrations of gadodiamide, and reference tissues within the field of view, such as ventricular blood, skeletal muscle, and subcutaneous fat. Evaluation resulted in T1 values of 881 msec ± 10 for myocardium prior to intramyocardial injection. As expected, this value did not change in remote myocardium after injection of gadodiamide solutions (880 msec ± 10, P = .8). Immediately after injection of gadodiamide solutions, the T1 value at the injection site declined significantly (P < .01) to 456 msec ± 5 after administration of 0.05 mmol/mL and to 228 msec ± 4 after administration of 0.10 mmol/mL (Figs 2, 3; Table 2). However, even on the Look-Locker images obtained 30 minutes after intramyocardial injection, the injection sites were clearly visible because of the still significant decrease in T1 values compared with those of remote myocardium. T1 values obtained after injection were significantly different between the two concentrations (P < .001).


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  		TABLE 2. T1 Values Calculated with the Use of Look-Locker Images

 


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  		Figure 2. Representative Look-Locker sequence MR images (3000/2.5; flip angle, 10°) obtained with a long-axis view of the heart. In the first image obtained after the inversion pulse (top left), the injection site cannot be differentiated from remote myocardium. The image acquired 228 msec after the inversion pulse (delay time after inversion pulse is in upper left corner of each image) shows the injection site (arrow) as dark because of faster zero crossing after intramyocardial injection of 0.10 mmol/mL gadodiamide solution at the injection site compared with remote myocardium. In consecutive images, the myocardium at the injection site gains bright signal intensity due to a shorter T1 value. The remote myocardium is dark at approximately 468 msec, corresponding to a T1 value of 885 msec ± 9 for myocardium. LV = left ventricle, RV = right ventricle.

 


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  		Figure 3. Plot shows changes in T1 values of myocardium at baseline and after injection of 0.10 mmol/mL and 0.05 mmol/mL gadodiamide (Gd-DTPA-BMA) solutions and remote myocardium during an observation period of 30 minutes (mean ± standard error of the mean). T1 values are significantly different for different concentrations at the same point in time of observation (P < .01) and increase significantly over the observation period (P < .05) because of diffusion and convection of the contrast medium. ms = milliseconds.

 
During the observation period of 30 minutes, T1 values at the injection site increased significantly (P < .05) (Figs 3, 4). At the same time, the extent of the contrast-enhanced region increased significantly (P < .05) during the observation period after injection of 0.10 mmol/mL gadodiamide and 0.05 mmol/mL gadodiamide (Fig 5). There was no significant difference in the size of contrast-enhanced myocardium after injection of 2 mL of 0.05 mmol/mL gadodiamide (15 mm2 ± 2) versus after injection of 0.10 mmol/mL gadodiamide (15 mm2 ± 2).



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  		Figure 4. Representative Look-Locker sequence MR images (3000/2.5; flip angle, 10°) obtained with a short-axis view of the left ventricle. There are two different injection sites: one immediately after injection of 0.1 mmol/mL gadodiamide (arrow) and one 15 minutes after injection of the same concentration (arrowhead). Zero crossing of the injection site immediately after injection is significantly faster compared with the injection site imaged 15 minutes after injection.

 


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  		Figure 5. Bar graph shows size of contrast-enhanced area after topical intramyocardial injection of 2 mL of 0.05 and 0.10 mmol/mL gadodiamide (Gd-DTPA-BMA) measured 3, 15, and 30 minutes after injection. Size of contrast-enhanced myocardium increased significantly (* = P < .05) during the observation period but was not significantly different between the two concentrations of gadodiamide (P > .1).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
REFERENCES
 
Interstitial injection of MR contrast media for monitoring the distribution of admixed substrates for local therapeutic interventions is a relatively new approach in interventional MR imaging. In contrast, interstitial injection of iodinated contrast medium mixtures is performed on a routine basis during computed tomography–guided sympathicolysis and nerve root blocking to monitor primary distribution of the injected anesthetics or ethanol (31). For MR-guided interventions, such as tumor ablation with ethanol, the intrinsic changes in signal intensity owing to the distribution of the injected substrate or tissue alterations after cell damage have been used for monitoring the effects of these interventions.

Direct injection of solutions with admixed MR contrast media has rarely been performed (32,33). However, with the current advent of gene therapy and related molecular interventions, local application of substrates is receiving increasing attention. The substrates are designed to initiate repair mechanisms, such as neovascularization or growth of myocytes, in the target area. With this new paradigm, dedicated minimally invasive techniques for local delivery, which allow for monitoring of the primary distribution of the substrate, are advantageous. It is evident that an unrecognized primary failure of delivery to the myocardium caused by intracavitary or intravascular injection can delay a sufficient therapy for weeks or months.

On the contrary, local "overdosing" of substrates may cause severe side effects. In a study conducted by Kloner et al (34), results showed that after intramyocardial injection of high doses of DNA that encoded vascular endothelial growth factor, local angioma formation occurred. In another study conducted by some of the same authors and at the same institution (35), it was shown that angiomas did not occur after intramyocardial injection of lower concentrations of the same substrate. An overdose of the substrates might be avoided by dilution on the injectate. However, it is important to avoid repeated injection into the same myocardial region. In this scenario, the requirements for a technique for local molecular interventions in the heart are as follows: provide a minimally invasive procedure that does not require general anesthesia, thus being repeatedly applicable in patients with coronary heart disease; provide direct delineation of the myocardial target area; provide delineation of primary distribution of substrate; and provide delineation of the spatial extent of injectate over the course of the intervention, to avoid multiple injections into the same region. To avoid repeated injections into the same regions, the injection site should be visible during the course of the intervention; thus, we observed the injection sites for 30 minutes in the current study.

In recent years, cardiac interventional MR imaging has been developed into interactive real-time imaging with high spatial and temporal resolution. These improvements open up the possibility to combine the intrinsically good soft-tissue contrast of MR imaging with the visualization of instruments for local application of substrates to the myocardium. In the current study, a radial real-time steady-state free-precession sequence allowed monitoring of the catheter introduction into the left ventricle, direct intramyocardial injection of gadodiamide-containing solutions, and delineation of intramyocardial distribution. Increased signal intensity at the injection site remained visible throughout the observation time. This property (the visibility of the injection site for 30 minutes) allows one to choose injection sites that are remote from each other and thus avoid potential local overdosing of injected substrate because of repeated injections.

If radial k-space trajectories are applied under conditions where each radial profile is acquired after excitation from the equilibrium condition, as it applies for steady-state free precession, signal intensity is high. The dominant type of artifact is radial streaking, which arises from periodic motion such as that from the cardiac and respiratory cycles (36,37). This type of artifact is easily recognized. Steady-state free precession, owing to basic MR physics, has a strong signal-to-noise ratio. These features render radial k-space sampling, combined with steady-state free precession, favorable in the current setting. To prevent undersampling artifacts in radial imaging (ie, aliasing), the largest angular step between the k-space trajectories must follow the Nyquist criterion. Thus, the same conditions as those for the read direction in the cartesian k-space coverage apply. However, with 80 continuous radial k-space lines, as used in the current study, spatial resolution is not compromised (24,36).

Signal intensity properties and contrast enhancement of steady-state free precession images are often considered to be "T2-like" but are primarily derived from the ratio of T2/T1. This renders steady-state free precession images sensitive to a signal intensity increase after administration of T1-shortening contrast media. As expected from this theoretical consideration, the distribution of contrast medium solutions was clearly visible on steady-state free precession real-time images. After intramyocardial injection of gadodiamide solutions, use of the Look-Locker sequence revealed significant decrease (P < .01) of T1 values at the injection site, which was sufficient for substantial increase of signal intensity to enable visualization on T1-weighted images. However, in each setting, the choice of concentration must be adapted to the sequence applied. The T1 values measured for the different concentrations of gadodiamide with the Look-Locker sequence may serve as a guide for this purpose, since they allow calculation of an expected contrast enhancement of the myocardium at the injection site compared with that of remote myocardium. According to the results obtained in the current study, concentrations of 0.05 and 0.10 mmol/mL are applicable for most T1-weighted sequences. However, the higher concentration resulted in a significantly stronger decrease in T1 values. At the same time, the size of contrast-enhanced areas was not significantly different for the injection of the two concentrations of gadodiamide. These findings suggest that washout of contrast medium might be dependent on concentration (38). Consequently, the higher concentration should be chosen if multiple injections are performed in a single session, and it is desired to avoid repeated injections into the same target area.

Interventional MR imaging was recently applied to local injection of a lentiviral vector into the wall of the iliac arteries. In that study, Yang et al (39) successfully used a 6% gadopentetate dimeglumine solution to delineate the distribution of the injected substrate and contrast medium mixture in the vessel wall. The concentration was similar to the one that was previously used for preparation of contrast medium solutions in phantoms or for inflation of balloons, that is, for solutions under stationary conditions (40).

In general, after direct injection into a tissue, the solution will distribute within the accessible space, which in normal myocardium is the interstitium and the vascular space. For normal myocardium, a two-compartment model can be assumed. However, in ischemically injured myocardium, the intracellular space of necrotic myocytes is accessible for the contrast medium, owing to loss of integrity of the cellular membranes (41). In addition, wall motion defects in infarcted tissue may cause slower washout of small molecules such as those of gadopentetate dimeglumine. Therefore, enhancement after injection of gadolinium-based extracellular contrast media to such myocardial regions will most likely yield higher signal intensities than the signal intensities achieved by injection into normal myocardium.

Further studies are necessary to evaluate signal intensity increase in ischemically injured myocardium after local injections. However, molecular interventions in most cases are targeted to viable cells. Therefore, injections may be performed in the close vicinity to necrotic areas but not within the necrotic tissue itself. A protocol that allows for delineation of infarcted areas and injection to the margins of these areas is required. Such a protocol could combine intravenous injection of contrast media for the differentiation of viable tissue and necrotic areas with the application of a real-time sequence. In further studies, the applicability of such a protocol will be shown. In the current study, perforation of the myocardium that resulted in hemorrhagic pericardial effusion occurred during one attempted injection into the myocardium. The self-made prototype needle catheter had no mechanism that could prevent perforation. A mechanical mechanism, such as a simple orthogonal barrier mounted on the needle, might prevent insertion too deep into the myocardium and perforation of the myocardium.

One limitation of the current study is the lack of ex vivo data. We did not mix the gadodiamide solutions with a tissue dye, which would have allowed for postmortem comparison between the extent of contrast-enhanced tissue on MR images and the extent of stained tissue. We did not perform such a comparison in the current study, since the close agreement between the size of contrast-enhanced tissue and that of stained tissue has already been shown previously (23). In addition, the fact that multiple injections at different times have been performed in animals would have allowed comparison of only the last injection with postmortem results. The current study was also focused on the time course of gadodiamide distribution and of T1 values rather than on the proof of the correlation of the region of signal intensity increase with the region of distribution of injected substance.

A second limitation of the current study might be that a rather conventional Look-Locker sequence was used. Scheffler and Hennig (42) have introduced inversion-recovery true fast imaging with steady-state precession for T1 quantification. They showed that their approach is less susceptible to systematic errors introduced by the disturbance of recovery of longitudinal magnetization by excitation pulses than are the usually used echo-planar or gradient-echo sequences (42). However, measurement of T1 values from skeletal muscle, as well as from subcutaneous fat and intraventricular blood, served as intrinsic control in the current study. Values obtained from these tissues are in close agreement with the T1 values obtained by other authors (29,43).

In conclusion, the results of the current study show that a catheter can be directed into the left ventricle by using radial real-time imaging and that substances such as diluted gadodiamide can be injected directly into the myocardium. At the injection site, T1 values of myocardium are changed depending on the concentration of the contrast medium. Changes in signal intensity remain visible for at least 30 minutes, but signal intensity decreases over the course of the observation period.

Practical application: The proposed technique of intramyocardial injection of solutions that contain gadodiamide may be used for the injection of substrates for molecular therapy of ischemic heart diseases to initiate angiogenesis and to attenuate left ventricular remodeling. Results of first clinical studies have already confirmed that the local injection of therapeutic agents provides benefits to patients (2,4,7,9). Further studies in large patient populations have to be conducted before this new form of therapy can be established in the clinical routine. However, before the proposed technique of MR-guided intramyocardial injection can be performed in patients, safe catheters have to be developed. Such catheters must provide a mechanism that prevents perforation of myocardium and must be MR compatible.


   FOOTNOTES
 
Abbreviation: ROI = region of interest

Authors stated no financial relationship to disclose.

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


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
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