Contrast-enhanced magnetic resonance angiography (ce-MRA) has become an established and routinely used imaging modality and has largely replaced invasive diagnostic digital subtraction angiography (DSA). There have been ongoing technical developments in magnetic gradient hardware, coil design and pulse sequence design for ce-MRA, resulting in an increased spatial and temporal resolution. The short intravascular half-life and the rapid interstitial distribution of conventional extracellular gadolinium-based contrast agents have limited the imaging time window and spatial resolution of ce-MRA. To overcome these limitations, several intravascular or blood-pool agents have been developed that allow longer acquisition time. In contrast to conventional extracellular MR contrast agents, blood-pool contrast agents are characterised by a longer retention in the vascular compartment. Blood-pool contrast agents are either paramagnetic or superparamagnetic. Paramagnetic blood-pool agents are typically gadolinium-based, whereas superparamagnetic agents are iron oxide particles. The longer retention of blood-pool agents in the vascular space is achieved by binding to macromolecules such as albumin, polysaccharides, polymers or lipids. Blood-pool contrast agents have a higher relaxivity than standard extracellular agents.1
Gadofosveset trisodium (Vasovist®, Bayer Schering Pharma AG, Berlin, Germany) is the first blood-pool contrast agent that has been approved in Europe for ce-MRA for the visualisation of abdominal or limb vessels in adults with suspected or known vascular disease.2 With blood-pool MR contrast agents, the imaging time for ce-MRA is prolonged. Thus, blood-pool agents provide the opportunity for alternative imaging strategies, such as navigator-gated MRA, which cannot be used with conventional extracellular MR contrast agents.1,3 Due to the longer imaging window and higher relaxivity, the spatial resolution of blood-pool agent-enhanced MRA might be increased. In addition to the first-pass bolus imaging phase, blood-pool agent-enhanced MRA can be performed at the steady-state imaging phase. This allows for a prolongation of the arterial examination and submillimetric spatial resolution. In addition, several MRA studies (e.g. time-resolved pulmonary MRA, high-resolution pulmonary MRA and whole-body MR venography) can be performed after a single bolus injection.4
Various classes of blood-pool agents have been developed that differ in their pharmacokinetic and physicochemical properties. Rapid-clearance blood-pool agents show a limited diffusion across normal endothelium, whereas their clearances are equivalent to the glomerular filtration rate. Examples for this type include macromolecular gadolinium chelates such as Gadomer-17 (Bayer-Schering-Pharma, Berlin, Germany) or P792 (Vistarem, Guerbet, Aulnay Sous Bois, France).
In contrast, slow-clearance blood-pool agents are more confined to the blood compartment, but their body clearance is restricted. As a consequence, the elimination half-life of these agents is prolonged. This category of contrast agents includes ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) such as NC100150, large polymeric gadolinium chelates and gadolinium chelates with reversible albumin binding, such as gadofosveset trisodium or B22956 (Bracco, Milan, Italy).5
Blood-pool Agent-enhanced MRA of the Abdomen
For the diagnostic assessment of the abdominal vasculature, ce-MRA – together with computed tomography angiography (CTA) – has become the clinically accepted standard of reference and has replaced conventional digital subtraction angiography. In abdominal aortic aneurysm or dissection, ce-MRA allows a simultaneous assessment of the aneurysmal extent and involvement of the renal, visceral or iliac arteries. With blood-pool agents, the first pass of the compound can be used for time-resolved MRA, allowing a dynamic assessment of the perfusion of the visceral organs and visualisation of blood-flow differences in the true and false lumen of aortic dissection.6 In patients with endovascular repair of abdominal aortic aneurysm, blood-pool agent-enhanced MRA might be more accurate for the detection of endoleakage than contrast-enhanced CT.7 In patients with artherosclerosis, the potential to increase the spatial resolution during the steady state promises a higher accuracy for the detection of vascular stenoses than conventional MRA with extracellular contrast agents. In patients with aortoiliac disease, Vogt et al. reported a higher agreement regarding stenosis location and degree of stenosis of gadofosveset trisodium-enhanced MRA and DSA compared with a non-contrast, time-off-light MRA.8 In another study by Nikolaou et al., gadofosveset trisodium-enhanced MRA showed a sensitivity of 97–100% and specificity of 96–100% for the assessment of high-grade stenosis in different vascular territories (e.g. carotid or renal arteries) compared with the clinical standard of reference. In this study the intermodality agreement between the gadofosveset trisodium-enhanced imaging and reference-standard imaging data was 90–93%.9
Renovascular hypertension is the most common form of secondary, and thus potentially curable, hypertension. In 90% of cases it is caused by a narrowing of the proximal part of the renal arteries – renal artery stenosis (RAS) – due to atherosclerotic changes. The remaining 10% are caused mainly by distally located inflammatory vessel lesions – fibromuscular dysplasia (FMD) – which mostly affects younger women.10 ce-MRA is the clinical gold standard for the detection of RAS.
Due to the limited breath-hold capacity of the patients, imaging has to take place during suspended breath-hold, limiting acquisition time and thereby reducing the spatial resolution. While proximal RAS can still be safely detected, FMD may potentially evade detection. Blood-pool contrast agents may overcome this limitation of MRA by facilitating longer respiratory-gated MRA acquisitions. Due to the widespread use of 3-D post-processing tools, the venous signal does not interfere with diagnostic image reading. In addition, the first pass of the contrast agent can be used to measure renal perfusion.11 Renal perfusion measurements are complementary to ce-MRA studies as renoparenchymal disease can also be detected. Thus, a comprehensive renal exam is feasible using a single injection of contrast agent. As the first pass of the contrast agent can be used for perfusion imaging and the steady state can be utilised for a high-resolution MRA, the total administered amount of contrast agent is lower than with comparable extracellular contrast agents. In addition, due to the high relaxivity of blood-pool contrast agents, only a fraction of the amount of gadolinium that would be required for extracellular contrast agents is needed. This could be of particular interest in view of the recently described disease ‘nephrogenic systemic fibrosis’, which is more likely to occur when higher doses of gadolinium are administered.12 Blood-pool agents may also be valuable in patients who are being evaluated as potential renal donors, as the entire abdomino-pelvic arterial and venous system can be examined after a single injection of contrast agent. This eases workflow and should eventually be more cost-efficient.
Blood-pool Agent-enhanced MRA of the Thorax
Blood pool agent-enhanced MRA can be used for the assessment of the aorta and pulmonary vasculature in the thorax in a similar way to how it is used in the abdomen.13 In particular, the assessment of the pulmonary arteries for pulmonary embolism is an interesting application for blood-pool agent-enhanced MRA. Although CT is nowadays the first-line imaging tool for the assessment of patients with suspected pulmonary embolism, ce-MRI is very appealing as it allows for a comprehensive radiation-free assessment of pulmonary perfusion and direct visualisation of embolic material in the pulmonary arteries using a single contrast agent injection. Moreover, MR venography of the deep venous system can be added for the assessment of underlying deep venous thrombosis without an additional contrast agent4 (see Figure 4).
Recently, an animal study indicated that the higher relaxivity of blood-pool contrast agents together with the increased signal-to-noise ratio of 3T effectively supports highly accelerated, parallel acquisition, time-resolved pulmonary MRA.14 For cardiac imaging, the direct visualisation of coronary arteries is a major challenge for MRI. Although multislice-CT coronary angiography is now the preferred non-invasive imaging technique for the assessment of coronary disease, blood-pool contrast agents may change the role of ce-MRA. Animal and volunteer studies of coronary MRA using blood-pool agents have been reported by different authors using different blood-pool contrast agents. Though heterogeneous in their set-up, all studies reported a significant advantage in coronary imaging compared with extracellular contrast agents.15–18 First results using navigator-driven 3- D MRA of the whole heart with considerable high resolution in patients look promising;19,20 however, a final assessment of the clinical value of this method is still pending.
Blood-pool contrast agents may further improve the potential of ce-MRA for the diagnostic assessment of the vasculature in the abdomen and thorax. The longer intravascular retention and higher relaxivity of blood-pool contrast agents can be used to improve the spatial resolution of ce-MRA. With the clinical introduction of blood-pool MR contrast agents, new applications for blood-pool contrast agent-enhanced MRA, such as comprehensive MRA of pulmonary embolism and venous thrombosis, may evolve.