Image-guided procedures are a minimally invasive form of treatment for diseased vessels and organs. Catheters, devices and therapies are introduced into internal organs via different routes and can be guided by real-time imaging. Image-guided procedures are consequently less invasive than surgical procedures and demonstrate similar patient outcomes. Recent percutaneous intervention studies showed steady increase in the usage of contrast media. Iodinated contrast media are routinely utilized in procedures guided by X-ray fluoroscopy and computed tomography, but these agents have nephrotoxic effects and require ionizing radiation to be visualized, which elevates cancer risk[2,3].
In the early 1980 magnetic resonance (MR) contrast media were introduced. MR contrast media exhibit paramagnetic properties that lead to contrast enhancement by shortening the longitudinal (T1) or transverse (T2) relaxation times. These agents rapidly pass to the extracellular compartment and are quickly eliminated by glomerular filtration. Unlike iodinated contrast media, they do not require ionizing radiation to be visualized. These agents are pivotal for accurate disease detection, pathology characterization and treatment planning. MR contrast media provide a wealth of tissue contrast that can be manipulated by the acquisition sequences. Refinements in imaging sequences can reduce the required dose of MR contrast media. This editorial summarizes the important applications of MR contrast media in MR-guided interventions and therapies.
MR CONTRAST MEDIA
MR contrast media represent alternative diagnostic options in patients at risk for adverse reactions to iodinated contrast media. In the early phase of using MR contrast media, the main problem was their toxicity because investigators used pure paramagnetic heavy metal ions. Later paramagnetic ions were chelated with DTPA, DOTA or BOPTA to reduce their toxicity. The chelation, however, reduced some of the paramagnetic properties of free ions. MR contrast media improve diagnostic accuracy, tissue contrast and visibility of inflammation, necrosis, tumor and vascular plaques.
In the late 1980 and early 1990 the first gadolinium-chelate was approved for clinical routine. Currently, the FDA has approved several extracellular gadolinium-chelates and only one gadolinium-based intravascular agent (gadofosveset trisodium). Other preclinical gadolinium-based intravascular media, which are used to extract physiologic and morphologic information are Gadomer 17 and P792. Extravasation and elimination of intravascular contrast media are very slow compared with extracellular contrast media.
In general extracellular gadolinium chelate and blood pool iron oxide particle MR contrast media have been safely and successfully used in patients. In 2005 the observation of nephrogenic systemic fibrosis (NSF), however, cautioned the handling of gadolinium-based MR contrast media[7,8]. NSF describes a systemic body collagenosis, most likely evoked by the deposition of gadolinium ions in the tissue. NSF was observed in patients with reduced renal function (eGFR < 30 mL/min) after the repeated injection of high doses of gadolinium-chelates. Besides the dose, the chemical structure of the chelate (defining the complex stability) has a major impact in increasing the risk of developing NSF. Thus, there is a strong need to minimize the dose of MR contrast media, especially in interventional procedures, where patients are subjected to repeated contrast injections.
Classification of MR contrast media is based on: (1) their distribution in the tissue compartments, namely the extracellular compartment (low molecular weight; < 2 kDa), intravascular compartment (high molecular weight; > 50 kDa), or intracellular compartment or (2) their effects on longitudinal (T1), transverse (T2) relaxation times and susceptibility shift (T2*) of tissues and thereby change tissue signal intensity[9,10]. While T1 shortening increases signal intensity, T2 shortening does the opposite. Extracellular or low molecular weight MR contrast media were widely used in interventional procedures, while intravascular or high molecular weight media, such as iron oxide particles, were used for cell labeling.
Iron oxide particles have been used as T1 and T2* MR contrast media to increase and decrease signal intensity of the region of interest on magnetic resonance imaging (MRI). Due to their size and composition, the particles remain in the intravascular compartment for a prolonged period. This class of agents has a high safety index and is not associated with NSF. There are two types of iron particles: (1) superparamagnetic iron oxide particles; and (2) ultrasmall superparamagnetic iron oxide particles. These agents are promising since their properties can be tuned for specific applications, such as cell labeling, drug targeting[11-13], tissue ablation and cancer therapy. They have also become MR markers of inflammatory and degenerative disorders associated with a high macrophage phagocytic activity.
APPLICATIONS OF MR CONTRAST MEDIA IN BODY INTERVENTIONS
Endovascular catheters and devices
A considerable research effort is directed at improving the detection of vascular disease with different imaging modalities, such as X-ray, computed tomography, intravascular ultrasound and MR angiography. Because of lack of harmful radiation and high soft tissue contrast, MR angiography is considered the most patient-friendly among these techniques. The main challenge for MR angiography is derived from the fact that the signal originates from water protons, which are abundant in the body. Inevitably, this leads to a background signal in the image and the blood pool cannot exclusively be seen.
Clinical and experimental studies showed that contrast enhanced MR angiography is possible for a selective and exclusive visualization of the vasculature. Delivering MR contrast media during catheter navigation can reduce image blurring and artifacts resulting from the movement of flowing blood, which allows for reaching the steady state earlier. Endovascular catheters and devices appear as dark objects in these cases. Furthermore, intravenous injection of MR contrast media during vascular intervention ensures procedure safety by enhancing the contrast between the vascular wall and endovascular catheter (Figure 1) and may prevent vascular perforation. Investigators coated the shaft and tip of endovascular catheters with either T2* or T1[19,20] MR contrast media to enhance the contrast between the blood pool and endovascular catheter, in which the devices appear either hypoenhanced or hyperenhanced based on the sequence and contrast media.
Figure 1 Selected magnetic resonance-guided images of the abdominal aorta prior to the administration of intravascular gadolinium-based (T1 enhancing agent) magnetic resonance contrast medium, the inflated balloon on the catheter is evident (arrow), but suffers substantial downstream signal loss (A).
After a blood pool magnetic resonance (MR) contrast medium administration (B), the MR dysprosium-chelate (markers placed on the catheter shaft) becomes evident (arrows, B) and, following inflation, the spatial extent of the balloon is better delineated (arrow, C).
A central challenge for the field of local therapy in tumors and cardiovascular diseases is the capability to visualize the catheter, target and targeting penumbra. MR contrast media showed promising results in visualizing, sizing and targeting penumbra (Figure 2), thereby allowing the interventionalists to determine the dose of the therapy based on size of the pathology. Furthermore, mixing MR contrast media with therapies may assist in ensuring tissue delivery and track its distribution over time (Figures 2 and 3).
Figure 2 Gadolinium-based magnetic resonance contrast media (T1 enhancing agent) have been used for multiple purposes in cardiac interventions.
A:These agents (at a low concentration) have been used to create a target in the myocardium; B: Gadolinium oxide powder was used to coat the endovascular catheter to facilitate navigation into the LV (white arrowhead); C: Magnetic resonance (MR) contrast medium was also used for enhancing and measuring the target (myocardial infarct) (white arrows); D: Selected MR-guided images show an active catheter hitting the infarcted target.
Figure 3 Selected magnetic resonance-guided images showing the advancement of a passive injecting catheter (arrowheads) in the left ventricle prior to (A) and after injecting dysprosium-chelate (T2* enhancing agent) magnetic resonance contrast medium (B, arrowhead) to ensure delivery in the targeted myocardium.
MR contrast media are useful in evaluating the efficacy of therapy by allowing the determination of tissue perfusion, blood volume, vascular permeability, angiogenesis and cellular integrity[21,22]. For example, after effective chemotherapy there is a decrease in the size of the lesion and number of microvessels, which can be detected on contrast enhanced MR images.
Transcatheter embolization of the uterine arteries for treatment of uterine fibroids was introduced 1995 in France and has been performed in the United States since 1996. This technique is currently used for treatment of symptomatic uterine fibroids and hepatocellular tumors. The standard protocol for evaluation of this intervention consists of dynamic gadolinium-enhanced 3D pelvic MR angiography and delayed contrast enhanced MRI. Prior to transcatheter embolization of the uterine arteries, contrast enhanced MRI is performed to confirm the diagnosis, map (determine the size, number and location of the pathology), predict treatment response (high signal intensity associated with poor response) and roadmap the pelvic vasculature. Embolization follow up showed that the procedure was successful when fibroids were unenhanced and the uterine arteries were invisible on perfusion MRI. In a rabbit tumor model, Chung et al used intra-arterial bolus injection of gadolinium-based MR contrast medium to measure uterine fibroid perfusion before and after uterine artery embolization. After positioning a catheter within the uterine artery and injecting the microemboli, they found that uterine tumor perfusion decreased by 76% on MRI. Others found that patchy perfusion suggests incomplete uterine artery occlusion and treatment failure[29,30]. This contrast enhanced MRI technique could be used to determine an optimal embolic endpoint with the long-term goals of improving uterine artery embolization success rates and minimizing procedure-related ischemic pain.
A major limitation of transcatheter arterial embolization is the inability to image and determine the in vivo fate of the injected emboli. Assessment of embolization relies on interpretation of visual blood flow information[23,31] and operator inferences. The limitations of transcatheter arterial embolization were demonstrated in a study probing the perceived and real completeness of uterine fibroid embolization. Investigators found incomplete embolization in 20% of cases despite indications by angiography of complete occlusion. They also found that incomplete embolization of uterine fibroids has led to tumor recurrence and persistence of symptoms, while exceeding the endpoint by injecting too much embolic material increases the chances of uterine damage. Until recently, there has been no noninvasive technique to track/map the distribution of embolic materials after intervention, which represents a significant disadvantage. Therefore, Fidelman et al impregnated the embolic materials (300-500 and 500-700 μm in diameters) with gadolinium-chelate by diffusion of the contrast medium into the core of the porous particles to visualize their distribution. Wilson et al used these impregnated embolic materials in visualizing the obstruction of different diameter blood vessels in the kidneys. These materials provided wave-front renal enhancement for > 1 h after injection. Large microemboli preferentially deposited in the medulla, while small microemboli deposited in the cortex. Renal blood flow was significantly reduced after the administration of 300-500 μm microspheres (from 3.9 to 1.0 mL/min per gram) and 500-700 μm microspheres (from 3.5 to 0.2 mL/min per gram) (Figure 4).
Figure 4 Distribution of magnetic resonance labeled embolic materials as a function of time in the left kidney.
Gadolinium-impregnated microspheres caused a steep increase in signal intensity over the cortical and medullary regions. Less than 5 min after the injection, as excess free gadolinium was excreted in the urine, the signal intensities began to decrease but still remained substantially above baseline for both particle sizes. Administration of magnetic resonance contrast media after the procedure confirmed the hypothesis that the injection of microspheres halts blood flow to targeted tissues. Hyperenhanced foci corresponding to microsphere location persisted for at least 1hr after injections. The smaller particles tended to settle more peripherally in the renal cortex, whereas the larger microspheres were lodged in the inner cortical and medullary regions. This new labeling technique may be useful for embolotherapy procedures, such as uterine fibroid embolization, hepatic tumor embolization, and preoperative meningioma embolization.
In 2008, Cilliers et al synthesized and characterized polyvinyl alcohol embolic particles modified with a clinically approved gadolinium-chelate MR contrast media. The investigators used these particles during transcatheter arterial embolization procedures. The polyvinyl alcohol particles are injected into tumor vessels and prevent blood flow, which results in tumor attenuation. They found that MRI of embolic particles facilitate determination of the endpoint of embolization, observe nontarget embolization, and improve the success rate of the procedure.
In 2011, Bartling et al presented embolization contrast media with a property of being visible on MRI and X-ray/computed tomography, namely iodine and iron particles. They proposed that implementation of this new material in clinical radiology will provide optimization of embolization procedures with regard to prevention of particle misplacement and direct intraprocedural visualization, while improving follow-up examinations by utilizing the complementary characteristics of CT and MRI.
An important clinical application of MR contrast media is that shown by Wilson et al, where patients with inoperable hepatocellular carcinoma were successfully treated using iron particles bound to doxorubicin. The particles ranged from 0.5-5.0 μm in diameter and were able to leave the vasculature under the influence of the force provided by the external magnet. Once the particles are outside the vasculature, doxorubicin desorbs from them, resulting in a local response with no systemic toxicity. Figures 5 and 6 show the setting of this clinical trial. Drug-bound iron particles can be precisely directed to selective organs by placement of an external magnet. In this study, MR contrast media showed the need for more therapy because of the lack of coverage of the entire tumor in the initial administration. MR images obtained after each dose of the chemotherapeutic agent showed increasing areas of signal intensity loss due to a magnetic susceptibility artifact caused by the iron.
Figure 5 This figure shows a portable magnet (left) and a diagram (right) depicts the mode of action of magnetic targeted therapy in the target.
The overall height of the magnet and holding apparatus is 1.4 m. The intra-arterial injected magnetic targeted carrier (iron particles) bound to doxorubicin (MTC-DOX), which is drawn out of the artery into surrounding tumor and/or liver tissue by the influence of the local magnetic field (Image courtesy of FeRx.). MRI: Magnetic resonance imaging.
Figure 6 Coronal magnetic resonance images of large hepatocellular carcinoma obtained before magnetic targeted carrier bound to doxorubicin administration (A) and after the first (B), second (C) and third (D) dose of magnetic targeted carrier bound to doxorubicin.
The selective hepatic arterial catheter was repositioned between each dose. The initial DSA image (E) was obtained during the injection of magnetic targeted carrier bound to doxorubicin (MTC-DOX) into the left hepatic artery supplying the tumor. The next dose was injected into the hepatic artery branch segment (F), while the third dose was injected into a branch of the right hepatic artery (G). As a result, progressively larger areas of the tumor were affected by MTC-DOX, as documented by the progressive loss of signal intensity due to iron susceptibility artifacts (T2*) on the intra-procedural coronal magnetic resonance images obtained after each injection.
Thermal ablation therapies (radiofrequency ablation, interstitial laser thermotherapy, microwave, cryotherapy and high-intensity focused ultrasound) are minimally invasive or non-invasive alternatives to conventional surgical resection. Ablation has been widely implemented in treating arrhythmia in the heart and tumors in the prostate, lung, liver, kidneys, etc. Contrast enhanced MRI has been successfully used to assess the success of ablation[37-39]. The diagnostic benefits of MR contrast media in differentiating ablated from non-ablated tissue have been confirmed in multiple centers[40,41]. Prior to the administration of MR contrast media, the appearance of thermally ablated tissue varies between hypointense, isointense and hyperintense. After ablation, MR contrast media provide moderate to intense enhancement of the rim surrounding the thermally ablated tissue. In a prostate cancer study, RFA ablated lesions appear hypoenhanced after gadolinium injection. Similarly, Goldberg and Dupuy observed a lack of contrast enhancement after gadolinium injection in ablated liver metastasis. Accordingly, changes in signal intensity, size, and internal contours of ablated tissue on contrast enhanced MRI gives important clues about the success of therapy.
Contrast enhanced MRI is also useful for arrhythmic substrate identification[45,46]. This technique has the ability to encompass the target volume through direct imaging of signal enhancement after tissue ablation in patients. Clinical studies have demonstrated the association between infarct scar, peri-infarcted zone and the risk of monomorphic ventricular tachycardia[46,48,49]. An integrated 3D scar reconstruction from delayed gadolinium-enhanced MRI was used to facilitate ventricular tachycardia ablation. van Dockum et al evaluated myocardial infarction induced by percutaneous transluminal septal myocardial ablation in symptomatic patients with hypertrophic obstructive cardiomyopathy using contrast-enhanced MRI.
A recent experimental study showed the value of MR contrast media in providing diagnostic information on an atrial septal defect, a congenital heart defect in which the wall that separates the atria does not close completely. Schalla et al found in an experimental study that gadolinium-filled balloon sizing is a useful method for detecting and sizing the atrial septal defects. They also used MR contrast media to demonstrate intracardiac left-to-right shunt prior to the placement of atrial septal defect device closure, where contrast enhancement of the right ventricle is detected simultaneously with enhancement of the LV (Figure 7).
Figure 7 Bolus administration of gadolinium-chelate demonstrates atrial septal defect on cardiac magnetic resonance four-chamber view images.
At the time of administration of the contrast medium, the right atrium was enhanced (A, arrow). Images acquired 1-2 s later show the contrast medium in both the pulmonary artery and left atrium (B, arrows) and subsequently in both right (arrow) and left ventricles (C). As a sign of an intracardiac left-to-right shunt, enhancement of the right ventricle is detected simultaneously with enhancement of the left ventricle. The re-enhancement of the right ventricle (D, arrow) as a result of recirculation of the contrast medium was acquired 12 s after image A.
Transendocardial and transvascular routes have been recently used to deliver MR labeled gene and cell therapies. The advantages of labeled therapies are: (1) targeting only pathologic regions; (2) delivering effective doses; and (3) reducing systemic side effects compared with IV injection[53-55]. Unlike intramyocardial injection, intracoronary artery injection of stem cells causes microinfarct, which was confirmed by increase in serum troponin I concentration and electrophysiologic abnormalities detected on electrocardiogram. Recent MR and MDCT studies showed the effectiveness of MR and CT contrast media in detecting and measuring microinfarct size[57,58].
MR contrast media showed great promise in detecting specific biological processes involved in the initiation and progression of atherosclerosis that may require intravascular intervention[59,60]. von Bary et al experimentally demonstrated the feasibility of noninvasive assessment of coronary remodeling, using elastin-binding gadolinium. Such data could facilitate the interpretation of clinical findings, enhance risk stratification and provide a means for local therapy. Monitoring extracellular matrix changes by contrast-enhanced MRI appears promising for the assessment of plaque burden in atherosclerosis or neointimal hyperplasia after coronary angioplasty and other therapies.
MR contrast media have also been used in quantifying the sizes of the area at risk, myocardial infarct and visualizing therapeutic delivery in the target. Saeed et al used MR contrast media in measuring ischemic and infarcted myocardium prior to and after transendocardial delivery of hepatocyte growth factor gene and endothelial growth factor gene using MR-guided procedures. They found that gene treated animals have better perfusion and significantly smaller infarct size than control animals on contrast enhanced MRI (Figure 8).
Figure 8 Gadolinium-enhanced magnetic resonance long-axis (left column) and short-axis (right column) images illustrate the extent of myocardial infarct (hyperenhanced myocardium) at 5 wk after infarction and 5 wk after injection of saline (top block, 4 magnetic resonance images) and angiogenic gene (bottom block, 4 magnetic resonance images).
Gadolinium-enhanced magnetic resonance (MR) images delineated myocardial infarct and showed substantial reduction in infarct extent and transmurality 5 wk after treatment (bottom block, bottom row, white arrows) compared with control animal (top block, bottom row). The angiogenic gene was delivered transendocardially under MR-guidance as shown in Figure 2. The histopathologic sections (right) show very few blood vessels in control animal (top right, black arrows) and the formation of abundant new blood vessels in gene treated animal (bottom right, black arrows).
MR contrast media have also been used to label cells in order to track their distribution in myocardium after intramyocardial injection under MR-guidance or intracoronary infusion[65,66]. Graham et al were able to follow the distribution of iron oxide labeled bone marrow progenitor cells for 42 d after intracoronary infusion. The transendocardial delivery route has been shown to be safe in patients with end-stage heart failure. Recent preclinical and clinical studies showed the importance of MR contrast media in determining the efficacy of stem cells[68-70]. First pass MR contrast media passage documented the benefits of angiogenic growth factors and angiogenic genes in increasing regional myocardial perfusion (Figure 9). Pearlman et al were the first to demonstrate the recruitment of collateral vessels after local delivery of angiogenic genes, using perfusion MRI.
Figure 9 First pass perfusion magnetic resonance imaging shows the hypoperfused infarct scar (arrows) after bolus administration of Gd-DTPA.
The magnetic resonance (MR) images illustrate the delay in the enhancement of infarcted myocardium (arrows) compared with remote myocardium. The images were acquired at 12 s (left) and 60 s (right) after bolus administration of MR contrast media.
Visualization of vascular anatomy, pathology (stenosis, aneurism, plaque) or implants (stents, filters, atrio-septal occluders or prosthetic heart valves) is crucial in interventional procedures. MR contrast media have been used in road mapping blood vessels[73,74], demonstrating vascular diseases and easing visualization of endovascular devices. These agents were delivered intravenously or intraarterially to enhance arterial[74,75] or venous vessels.
Inflammation is a key process in atherosclerotic progression and has been associated with increased frequency of plaque rupture. Ultrasmall superparamagnetic iron oxide particles have been used in characterizing atherosclerotic plaques from many different perspectives. These agents are effective markers of plaque inflammation. Different plaque tissues can then be characterized based on their enhancement properties.
Both gadolinium and iron oxide based contrast media are useful for labeling different types of cells that assist in cell tracking[79,80]. These agents have no negative effects on cell viability, proliferation or differentiation[81,82]. The toxicity of iron oxide particles is less than free gadolinium because free iron particles released from dead iron labeled cells are recycled in the body and not associated with NSF.
MR contrast media can be introduced into the intracellular compartments by endocytosis, phagocytosis or magnetoelectroporation. Investigators found that the duration of detection of labeled cells on MRI varies from 5 wk for embolic stem cells to 16 wk for skeletal myoblasts. Modo et al observed that gadolinium chelate labeling allows in vivo identification of transplanted neural cells up to 1 year after transplantation in rats with middle cerebral artery occlusion. Bulte et al found that the reliable detection limit of a cluster of iron oxide-labeled cells in beating hearts at clinical field strengths is on the order of 100 000 cells. Iron labeling of stem cells generates a hypointense signal (dark region), related to the susceptibility effect of the particles, on T2*-weighted images. Iron oxide particles provide T2* parametric map for up to 3 wk[79,86,87]. In the future, accurate depiction of treated regions with MR labeled cells may permit rapid adjustments of the therapeutic regimen to improve clinical outcomes.