Use of a drug or contrast agent for a listed contraindication or excluded use cannot be considered to be off-label; they are against label however they might still be necessary and patient-specific appropriate if used with the proper diligence. A new situation arose when the FDA decided to put a black box warning label on all gadolinium-based contrast agents in 2007 as a response to the occurrence of cases with NSF (nephrogenic systemic fibrosis).⁶ Before we review the current status of this severe adverse reaction to gadolinium-containing MR contrast agents, let us finish with the labeling aspects. What is the intent of such a warning and what does it mean from a practical point of view? First, it is the strongest warning mechanism that the regulatory agencies have to ensure the user/health care professional is aware of a change in a label and product or class-associated warning, and second, gives regulatory guidance on the appropriate use. The FDA black box label means, for example, that any contrast dosage outside the contrast agent-specific label cannot be considered off-label anymore but will have to be considered against the label. In summary, the country-specific label of an MR contrast agent must be known and appropriately considered in the clinical practice of cardiovascular MR/MRA and will continue to change.

Safety of MR Contrast Agents

Although any contrast agent that received marketing approval needed to previously prove safety and identify use and warnings labels, cardiovascular MR imaging had its share of specific issues in the recent past that are highlighted to raise proper awareness and understanding in managing patients with cardiovascular disease.

The nonimaging community was warned in a 2003 letter to the editor of the New England Journal of Medicine that severe pseudohypocalcemia was observed after gadolinium-enhanced MRA.⁷ The authors noted lower calcium values in blood samples obtained in patients immediately after they had an MRA performed with gadodiamide (Omniscan, GE Healthcare Medical Diagnostics) as MR contrast agent. The interaction of excess chelate in the gadodiamide with colorimetric calcium tests was recognized by experts but was neither included in the product label nor commonly known and caused multiple issues, especially in patients who had undergone CE MRA.⁸^,⁹ A subsequent letter and editorial revealed that these drug laboratory test interactions are not specific to MRA, but to two contrast agent formulations, gadodiamide and gadoversetamide (Optimark, Mallinckrodt) that interact to lead to false lower calcium levels in colorimetric but not in ionic calcium tests.¹⁰ These observations and subsequent public discussion can be credited with increasing awareness about MR contrast agent safety, which was perceived as entirely safe with considerable complacency evolving.

One of the most essential safety aspects of a contrast agent is that it needs to be completely eliminated after injection into the patient. Although this sounds trivial, imaging agents did have some dark clouds in their history when thorium dioxide (Thorotrast, Heyden) was discovered and subsequently used as a capable x-ray contrast agent, however, its retention in the body and radioactivity (alpha-particle) was not readily recognized in the early part of the last century.¹¹ Most MR imaging agents including gadolinium chelates are eliminated via renal clearance; iron oxides, with the liver and reticuloendothelial system (RES). It is important to understand the specific characteristics and elimination pathway of an agent as well as what happens if elimination is impaired. Therefore, it should not be a surprise that a drug that depends on renal elimination has the potential to change its biologic behavior if the pathway is impaired, consequently making agents with multiple or other elimination pathways highly desirable for patient populations with renal impairment. Contrast agents should always be given at the lowest effective dose to enable diagnostic-appropriate visualization of the target organ system, here the cardiovascular system; however, at this juncture, is also the pitfall. For a time some in our community suggested that “more is better” which frequently did improve the image quality obtainable by still evolving MR methodologies, however, the safety profile does change with changing populations and dosages. Similar to the speed rating of a tire, safety of medications can and does vary when we use it beyond recommended usage. From a safety perspective, the rapid elimination from the body, no or limited drug to drug interactions and no or limited toxicity are the key desirable safety aspects of a contrast agent.

Pharmacovigilance of MR Contrast Agents

Pharmacovigilance is the analysis of observed adverse events of an available drug, in this case MR contrast agent, and is the methodology employed to monitor the safety when a drug is broadly available. It is still a growing science as we continue to learn more about how to assess, manage, and predict the safety of drugs in large, diverse patient populations and with considerable changes in the way we practice medicine. Aside from post-marketing, phase IV studies, the information source is solely based on adverse event reporting. A healthcare provider is encouraged and sometimes mandated by country-specific laws to report any adverse event observed during the clinical use of medications/drugs—either directly to the vendor or to a regulatory body sponsored website such as MedWatch by the FDA.¹² Although this spontaneous adverse event reporting has its shortcomings, it is the best and only broad-based mechanism currently available. Unfortunately, drug manufacturers and, as such, also the vendors of MR contrast agents do not commonly voluntarily release their adverse event reporting database which they are required to compile on a global basis. The manufacturer does know how many doses of a drug are sold and those sales data are then related to the adverse event reporting rates. In an adverse event report, the reporter documents the observations, some patient characteristics, severity of the adverse event, and assesses the relationship to the contrast agent. Depending on the severity and expectancy of the adverse event, the regulatory agency and/or manufacturer may further investigate such a report. As part of country-specific marketing approvals, a manufacturer may have to report the noted observations, however these are typically not publically available documents. The largest released reporting of pharmacovigilance data on an MR contrast agent is available on the use of Gd-DTPA (Magnevist, Bayer HealthCare Pharmaceutical) and has been voluntarily reported. These data indicate for specific event categories, such as cardiovascular reactions rates, of 4 to 8 events per 100,000 doses administered.¹³ Renal impairment was identified in adverse event reports from 0.1 to 0.8 events per 100,000 doses and was with angioedema, the only major category that showed an increasing trend in the recent years of adverse event reporting. Further analysis of those reports indicating renal impairment revealed that patients most commonly had preexisting renal conditions due to nephrotoxic medications and were receiving higher than labeled contrast agent doses. Unfortunately, these data are not publically available for the other commonly used MR contrast agents. The current annual global use of MR contrast agents is estimated to be around 12 million patient doses. Although no broad-based data are currently available on the cardiovascular MRA examinations being performed, estimates suggest an annual rate of about 2 to 3 million procedures. In order to further put adverse event reporting in perspective, it must be highlighted that those for the Gd-DTPA MR contrast agent are two to three times lower than those reported for nonionic monomeric iodinated contrast agents used in x-ray, and allergic reactions are reported about eight times more frequently for nonionic iodinated contrast media used in x-ray than for the Gd-DTPA, an MR contrast agent.¹⁴ Anaphylactoid reactions have been seen in Gd-DTPA at a reporting rate of 3 to 4 per million, whereas urticaria has been reported at a rate of 29 to 79 per million.

NEPHROGENIC SYSTEMIC FIBROSIS (NSF)

Nephrogenic systemic fibrosis (NSF) initially also referred to as nephrogenic fibrosing dermopathy (NFD) is a condition that, to date, has occurred only in people with kidney disease. NSF is a systemic disorder with its most prominent and visible effects in the skin, hence its original designation as a dermopathy.¹⁵ Our current knowledge recognizes that kidney disease seems to be a prerequisite for developing NSF and, therefore, it has been accepted as the terminology most reflective of the reality of the disorder. Although the pathophysiology of this disease mechanism is not yet fully understood and is still evolving, it is simultaneously subject to intense litigation, such as those consolidated by a judicial panel to the U.S. District court in Cleveland, Ohio.

As the knowledge continues to evolve, it is important for the reader to review current literature to ensure being aware of recent observations. The following paragraph summarizes the current and broadly accepted knowledge.

Neither the duration of kidney disease nor its underlying cause appears to be related to the development of NSF. No specific form of dialysis has been linked to NSF, although most patients with NSF do undergo dialysis procedures which are coinciding with severe renal impairment. Some patients who have never been dialyzed have developed NSF. NSF affects males and females in approximately equal numbers. NSF has been confirmed in all age groups but tends to affect the middle-aged population most commonly. It has been identified in patients from a variety of ethnic backgrounds from North and South America, Europe, Asia and Australia with the majority of reported cases occurring in the United States.

The current concepts on the underlying causative factors are the combination of two factors: severe renal impairment and exposure to gadolinium. Gadolinium (Gd), an element of the lanthanide series (atomic number 64), is used in nearly all currently marketed MRI contrast agents. It is always used in a chelated form because it is toxic in its free form. All standard, nonprotein interacting Gd-chelates are virtually entirely excreted via the kidneys; therefore any impairment leads to increased in vivo retention and circulation times. If there is no residual urine output, the only way such agents can exit the body is through dialysis. In patients with normal kidney function, the Gd-chelates are considered safe because the bond between the toxic Gd atom and its ligand molecule is very strong; however, differences between agents are established. There is a small risk that Gd atoms can unbind from their carrier ligands and the unbound “free” Gd reacts like calcium ions, most likely binding to readily-available phosphates and forming insoluble molecules. In patients who receive large doses of Gd-chelates and who do not undergo rapid and effective dialysis, there is a risk that larger amounts of these gadolinium compounds could develop and remain in the body in a form that is not readily removable. Although several Gd-chelate formulations exist as detailed subsequently, only some appear to be more frequently associated with NSF, and only one, gadodiamide, has been associated with the vast majority of cases of NSF. Some clinicians have suggested that because this agent is slightly more likely to dissociate chemically, Gd dissociation (de-chelation) might be the trigger of NSF at the cellular level; however, this aspect is currently not only in scientific but also in legal discovery discussion. Another relevant drug to drug interaction might be caused by the co-administration of erythropoietin (EPO) and intravenous iron. Erythropoietin has the potential to affect the growth of other cells in the bone marrow and curiously, the cell responsible for producing much of the collagen deposition seen in NSF develops in the bone marrow. Initial preclinical experiments indicate that EPO could facilitate the development of NSF in some cases by increasing the number of circulating fibrocytes.

Besides kidney disease, medical conditions that may be associated with NSF include hypercoagulation abnormalities and deep venous thrombosis, recent surgery (particularly vascular surgery), recent failure of a transplanted kidney, and sudden onset kidney disease with severe swelling of the extremities. It is very common for the NSF patient to have undergone a vascular surgical procedure (such as revision of an arteriovenous fistula, or angioplasty of a blood vessel) or to have experienced a thrombotic episode (thrombotic loss of a transplant or deep venous thrombosis) approximately 2 weeks before the onset of the skin changes.

The underlying clinical question as identified in the cases above frequently justifies the use of gadolinium-enhanced MRI or MRA studies. Whether there is an independent risk associated with endothelial damage or hypercoagulation remains an open question, although circulating fibrocyte migration from the blood is facilitated in both scenarios. In summary, the pathophysiological trigger and disease mechanism is still under investigation and our knowledge continues to evolve.

The current status with a focus on cardiovascular imaging in regard to the NSF risk of Gd-containing MR contrast agents (GBCA) can be outlined in the following way. First, we need to confirm prior to any administration of GBCA that the patient does not have a severe renal impairment. Our community has and is evolving guidance on how to most appropriately manage this risk assessment. The wide availability of point-of-care testing for serum creatine levels and the estimated glomerular filtration rate (eGFR), enables a just-in-time risk assessment. It appears prudent at the current time that in outpatients, a recent (less than 3 months old) blood lab readout of serum creatine (and eGFR) should be available. However, in patients being imaged for a cardiovascular question, a concomitant renal ailment might be rapidly evolving, the patient might have recently received medications or undergone other diagnostic studies such as contrast-enhanced CT or diagnostic angiogram using iodinated contrast agents and the patient could have experienced a new renal impairment. In such situations, as well as in instances in which a patient has undergone multiple imaging examinations, a very recent eGFR is strongly recommended. As highlighted in the FDA warning, a GFR below 30 mL/min/1.73 m², which means patients with chronic kidney disease (CKD) of 4 or 5 or patients who have had or are waiting for a liver transplantation, have an elevated risk for this severe adverse event. Some investigators see patients with CKD 3 or a GFR between 30 to 60 mL/min/1.73 m² as a potential or lower risk group.

The issue of multiple imaging studies in short time periods is evolving as a safety concern in that potential cumulative effects are difficult to study and are frequently superimposed on other underlying medical ailments. Therefore, it is also highly advisable to have a current eGFR available in such patients.

How to most appropriately handle the medical indications to use Gd-chelates in patients with renal impairment requires a patient-specific assessment and continues to rapidly evolve. As with all procedures that have elevated risks, a patient-specific risk-benefit analysis must be done by the physician prescribing the MR contrast agent and current literature should be consulted. In addition to the already identified medical conditions, special considerations need to include a review of frequency of imaging studies and potential drug to drug interactions, patient compliance, and appropriate follow-up capabilities. There are alternate MR contrast agents on the horizon that are iron oxide-based and do not use the renal elimination pathway that appear promising for use in the patients with severe renal impairment. Although non–contrast-enhanced MR angiography is frequently not as capable as CE MRA, it still might be the most appropriate alternative if ultrasound-based imaging cannot clarify the medical question to be resolved. In summary, the awareness of the potential for NSF has substantially changed our practice with the unambiguous need to be able to identify patients with renal impairment prior to dosing with Gd-chelates, the need to follow the labeled use and indications as well as being more aware of cumulative effects of multiple imaging studies and/or drug to drug interaction.

Cost

The cost of MR contrast agents varies regionally and is strongly dependent on the degree of discounting. All MR contrast agents have weight-based dosing in the label and most pharmaceutical companies manufacture contrast agent vials in different sizes. Multi-vial dosing combined with patient-specific dosing can be accommodated if appropriately approved injection/infusion systems are being used. It can be further anticipated that upcoming contrast agents will use alternate elimination pathways or will be capable of use at substantially lower concentrations, albeit at a cost premium to existing contrast agent options.

First Pass versus Steady State Imaging

The time window of increased vascular signal enhancement is a critical component for MRA. Although this time window is influenced by the injection/infusion protocol used, the dosage, and cardiac output, it is most importantly dependent on the kind of contrast agent used—a first pass agent or a blood-pool agent. The vast majority of MRA development and clinical use has been done as first pass imaging. The availability and market introduction of gadofosveset trisodium has for the first time enabled a combined clinical first pass and steady-state imaging of the vasculature. The challenges and opportunities of steady-state imaging will be discussed in other chapters of this book. The next sections will focus on the specific characteristics of the different MR contrast agents and are approached by classifying the agents into appropriate groupings.

CLASSIFICATION OF MR CONTRAST AGENTS FOR CARDIOVASCULAR IMAGING

MR contrast agents currently fall into two broad categories; those based on gadolinium, which are predominately paramagnetic in nature, and those based on iron oxide particles of different coating and size that are superparamagnetic (Fig. 18-1). The broadest use for cardiovascular imaging is based on gadolinium chelates which can be subclassified into agents revealing no interaction with proteins, those that have weak temporary interaction with proteins leading to increased relaxivity and/or having an additional extrarenal elimination pathway, and those that have strong protein binding. Table 18-1 summarizes the contrast agents that are currently available or have been in clinical trials at varying stages relevant for cardiovascular MR imaging.¹⁶

FIGURE 18-1 Classification scheme for MR contrast agents that are potentially applicable to cardiovascular imaging. The paramagnetic gadolinium chelates can be classified according to their degree of protein interaction. The ultra-small iron oxide particles are “blood pool agents” that demonstrate long intravascular enhancement.

TABLE 18-1 Physicochemical Characteristics of Clinically Developed Gadolinium-Based MR Contrast Agents

Currently, nine GBCAs are approved in one or more countries. Seven of those have been developed as multi-purpose imaging contrast agents and all have at least neuroimaging as a labeled indication. Two gadolinium chelates are approved with targeted indications, gadoxetate disodium (Eovist, Bayer Healthcare) as a liver-specific imaging “to detect and characterize lesions in adults with known or suspected focal liver disease and gadofosveset trisodium (Ablavor, Lantheus) as an MRA agent “to evaluate aortoiliac occlusive disease (AIOD) in adults with known or suspected periperipheral vascular disease.”

Nonprotein Interacting Standard Gadolinium Chelates

This group of “conventional” gadolinium chelate agents was introduced more than 20 years ago with nearly simultaneous approval of gadopentetate dimeglumine (Gd-DTPA, Magnevist, Bayer Healthcare) in all three key markets: European Union, United States, and Japan. Five of these agents are available as 0.5 molar formulations and one, gadobutrol (Gd-BT-DO3A, Gadovist, Bayer Healthcare) is being marketed at a 1.0 molar formulation. Although differences exist between these agents in terms of the molecular structure and chemical and physical properties (Tables 18-1 and 18-2), all agents are nonspecific and are eliminated unchanged via the renal pathway by glomerular filtration. The T1 relaxation rates of these agents are comparable and fall in the range between 4.3 and 5.6 L/mmol · s⁻¹. These similarities lead to equivalent imaging characteristics at the same dose and injection rate.

Table 18-2 Physicochemical Characteristics of Small and Ultra-Small Particles of Iron Oxides Developed as MR Contrast Agents

From the molecular structure, the agents can be subclassified into ionic or nonionic, linear, or macrocyclic. The concept of the nonionic agents was that they would have an even better safety profile with fewer adverse events comparable to the impact of reducing ionicity in iodinated contrast agents. This idea could not be realized with the agents and the stability of the binding of the gadolinium central atom has become much more critical. From this perspective, the nonionic linear molecules are the least stable and the ionic macrocyclic agents are the most stable. Therefore, the binding strength of the gadolinium by its surrounding chelating complex has become a differentiating factor. The two agents, gadodiamide (Gd-DTPA-BMA, Omniscan, GE-Healthcare) and gadoversetamide (Gd-DTPA-BMEA) have substantially lower binding and, therefore, include excess chelate in the formulation to trap any dissociated gadolinium ion in the vial which has also been the causative factor for the interference with colorimetric calcium tests and the spurious hypocalcemia.¹⁰

Gadobutrol (Gadovist, Bayer Healthcare) is the only agent that is available at 1.0 molar formulation that enables twice the concentration of gadolinium to be delivered into the vasculature per unit volume, thereby enabling a stronger vasculature signal for perfusion and vasculature imaging, which has led to the initial preferred use of this type of agent for susceptibility weighted perfusion imaging of the brain.

Gadolinium Chelates with Weak Protein Interaction

This class represents a second generation of gadolinium chelates that possess a higher T1 relaxivity in blood such as for gadobenate (Gd-BOPTA, Multihance, Bracco) (9.7 L/mmol · s⁻¹) due to the weak transient interaction between the agent and serum proteins, particularly albumin and a T1 relaxivity of 8.2 L/mmol · s⁻¹ in human plasma for gadotexetate disodium (Eovist, Bayer Healthcare). Both agents are ionic, linear chelates and have a dual elimination pathway with partially hepatobiliary elimination, gadobenate is weaker than gadoxetate. The higher T1 relaxivity manifests as a significantly greater intravascular signal intensity enhancement compared to that achieved with conventional gadolinium chelates at equivalent doses with the benefits of a more pronounced effect in smaller vessels as well as in the margins of the tumors. To objectively assess if differences in intravascular image contrast exist between the first group of standard gadolinium chelates and the new group, an intraindividual cross-over study was performed that revealed that gadobenate dimeglumine presented a significantly more intense contrast enhancement with a higher, longer peak duration and larger area under the vascular contrast enhancement curve.¹⁷ This finding was confirmed in subsequent larger MRA studies for the run-off vasculature,¹⁸ pelvic and carotid vasculature. The practical impact is that for the same dose and administration approach, a more intense and longer duration intravascular signal intensity benefit was noted. The clinical advantages of the increased relaxivity also have been demonstrated for many vascular territories that range from the carotid vasculature¹⁶ to the distal run-off vessels.¹⁶ Like the conventional nonprotein interacting GBCAs, gadobenate dimeglumine has an excellent safety profile with a very low incidence of adverse events noted for the clinical development program as a whole,¹⁶ however the potential risk to cause NSF cannot be excluded and the same level of diligence also applies to this group. The fact that more signal/enhancement can be obtained for the same dosing more readily enables full diagnostic quality at lower doses, thereby reducing dose and accumulation-dependent potential effects.

Gadoxetate disodium has only recently been developed and is being marketed in many countries for liver imaging and is packaged in a 0.25 mol/L concentration, one half that of the standard GBCAs. This agent is not currently being used nor has it been clinically evaluated for cardiovascular imaging; however, it can certainly be used for MR angiography associated with liver imaging.

Gadolinium Chelates with Strong Protein Interaction

The contrast agents in this category exhibit strong affinity for serum proteins which increase the relaxivity and also have extended intravascular half-life making them by design cardiovascular imaging agents. Gadofosveset trisodium, developed under the identifier MS-325 (then under the proposed product name of Vasovist and now under the new product name of Ablavar) has gone through full clinical development and is approved in several countries, including the United States, for specific MRA indications. This agent is available in a 0.25 mol/L concentration, has been reported to be 88% to 96% noncovalently bound to albumin in human plasma and to exhibit a relaxivity at 0.5T that is 6 to 10 times that of gadopentetate dimeglumine. The agent has a recommended dosing of 0.03 mmol/kg body weight ¹⁹ and achieves its desired intravascular contrast at a substantially lower dose because of its higher relaxivity. The elimination pathway is primarily renal but it also has some hepatobiliary elimination. This agent can be used for first pass contrast-enhanced MRA and for steady-state imaging in a number of vascular territories. Although this agent has been investigated in trials in many vascular territories, its 2008 FDA approval and label states the indication as “MRA to evaluate aortoiliac occlusive disease (AIOD) in adults with known or suspected peripheral vascular disease”. The European Medicines Agency (EMA) had already approved the agent in 2005 with the labeled indication “for contrast-enhanced magnetic resonance angiography for visualization of abdominal or limb vessels in patients with suspected or known vascular disease”, which is a much broader indication. The agent also exhibits an extravasation in the case of blood brain-barrier breakdown and is currently the only approved agent that will allow first pass and steady-state imaging.

The second agent with strong affinity for serum proteins and increased relaxivity is gadocoletic acid (B22956, Bracco). This agent has undergone phase II trials for enhanced coronary MRA and has been shown to have even stronger affinity for serum albumin than gadofosveset (approximately 94% bound noncovalently) with a similarly long intravascular residence time.²⁰

There are two principal types of paramagnetic “blood pool” contrast agents: those whose intravascular residence time is prolonged due to a capacity of the gadolinium chelate for strong interaction with serum proteins, and those that have a macromolecular structure whose large size limits the extent of extravasation compared to the first pass gadolinium agents. Another important factor to characterize blood pool agents is in their capability and efficacy to be used in first pass as well as for steady-state vascular imaging.

Gadolinium Contrast Agents with Macromolecular Structures

Examples of gadolinium-based blood pool agents with macromolecular structures are P792 (Vistarem, Guebert) and Gadomer-17 (Bayer Healthcare).¹⁶ These agents differ from the currently available low molecular weight gadolinium agents in possessing large molecular structures that prevent extravasation of the molecules from the intravascular space following injection, but do have slow, reduced leakage in case of blood-brain barrier breakdown. The molecular weights of P792 and gadomer-17 are 6.5 kDa and 35 kDa, respectively, which compare with weights of between approximately 0.56 kDa and 1.0 kDa for the purely first pass gadolinium agents. Whereas the structure of P792 is based on that of gadoterate substituted with four large hydrophilic spacer arms, gadomer-17 is a much larger polymer of 24 gadolinium cascades. In addition to differences in molecular weight and structure, these two agents appear to differ in terms of their rates of vascular clearance, with P792 considered a rapid clearance blood pool agent. Despite these differences, both agents have cardiovascular imaging capabilities and have been evaluated for these indications in clinical trials. Currently, it is not clear if and when any of these agents will receive regulatory approval or would be marketed.

Superparamagnetic Iron Oxide Agents

The second major category of potential contrast agents for cardiovascular imaging consists of the superparamagnetic group, which is based on particles of iron oxide (PIO) that are differentiated by the size and by its coating and are frequently also referred to as nanoparticles. Those with a diameter larger than 50 nanometer are referred to as small (SPIO) and those smaller as ultra-small (USPIO). Iron oxide particles have either a starch, dextran, or carbohydrate coating and its biologic characteristics are predominately dependent on its coating, whereas its imaging characteristics as either beneficial for T1-weighted or T2*-weighted imaging, is based on its size.

The first approved and marketed iron oxide-based contrast agent was AMI 25, also known as ferumoxide and marketed as Endorem (Guebert) or Feridex (Bayer Healthcare), with an indication for T2*-weighted liver imaging. This SPIO has also been used for cell-tracking and has a demonstrated potential for molecular-based cardiovascular imaging applications.²¹ Although there were no regulatory issues, the sole manufacturer of this agent, AMAG Pharmaceuticals, decided in November 2008 to cease its manufacture.

The second available iron oxide was developed under the code name of SHU555, also known as Ferrixan or Ferucarbotran, and subsequently marketed as a liver imaging agent under the brand name of Resovist (Bayer). These superparamagnetic iron oxide particles are coated with carboydextran and are accumulated by phagocytosis in cells of the reticuloendothelial system (RES) of the liver. The product formulation had a distribution of particle sizes that predominately led to the RES uptake. However, a filtered subfraction of this agent SHU555 C consists only of USPIOs and has been developed as a cardiovascular imaging agent for first pass and steady-state MR angiography. Another USPIO with starch coating was developed for MRA known as Feruglose, NC100150 or Clariscan, however development was discontinued after substantial longer term liver retention was observed.

All iron oxides have been used as carrier molecules for targeted imaging and it remains a highly exciting research area with great potential for molecular targeted cardiovascular imaging. AMI 227 (Ferumoxtran), also known as Combidex or Sinerem, is another USPIO that has been specifically evaluated for lymphatic MR imaging ²²^,²³ but has not yet received final regulatory approval. The fifth iron oxide agent that has been evaluated for MRA imaging is ferumoxytol, formerly known as Code 7228 and now as Feraheme (AMAG). Although its initial development goal envisioned it to be an imaging agent, it was subsequently developed as an iron replacement therapeutic drug indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD), the very same population at higher risk for NSF from Gd chelate imaging agents. This agent received its therapeutic FDA approval in 2009 and is being marketed with its labeled therapeutic indications. The potential for cardiovascular applications of this agent are high because it has a first pass and steady-state imaging ability and a well established safety profile at even higher doses than needed for imaging in a high-risk population for Gd chelates. Overall, it can be speculated that iron oxides, especially the USPIOs, will have an important place in cardiovascular MRA in the future, not only for intravascular contrast but also as a molecular targeted MR contrast agent. The contrast agent field will continue to evolve and the efforts over the last decade are leading to exciting new, safe, and robust imaging approaches, further increasing the clinical importance of safe, effective, and noninvasive MR cardiovascular imaging.

Although contrast agents for both CT and MR did not reveal distinctively different imaging characteristics in the past, now new agents provide truly distinctive characteristics that advance the capabilities in noninvasive disease detection and characterization. The advent of molecular targeted agents is on the horizon for cardiovascular cross-sectional imaging that will enable us to further improve imaging capabilities.