Systemic atherosclerosis involves all major arterial vessels, including the carotid and intracranial arteries, coronary circulation, thoracic and abdominal aorta, internal iliac arteries, renal arteries and peripheral vasculature. This generalised disease contributes to cardiac ischaemic disease, stroke, limb loss and a range of other illnesses, and is the major cause of morbidity and mortality in western countries.1,2
In the past few decades, conventional catheter angiography with an iodinated contrast agent (CA) was the standard clinical practice when detailed imaging of the vasculature was required. Recently, less invasive techniques such as computed tomography angiography (CTA) or magnetic resonance angiography (MRA) have been developed. Owing to the lack of ionising radiation and iodinated CAs, MRA is perceived as the optimal solution to perform one-stop non-invasive imaging of the arterial vessels.3–6 Following the groundbreaking technological innovations over the last few years, MRA has experienced rapid growth, and the advent of dedicated hardware and fast sequences for angiographic examinations and the implementation of integrated parallel imaging techniques (IPATs) has led to a variety of new applications.
MRA does not necessarily require contrast material, but contrast-enhanced MRA (CE-MRA) has become the standard practice because it is faster and flow-independent. The diagnostic accuracy of this approach has been positively evaluated in a number of studies. However, with the use of conventional interstitial CA, the diagnostic performance of CE-MRA is a function of temporal and spatial resolution, anatomical coverage and acquisition time. This relationship is often in conflict with the transit time of the CA and the breath-hold capacity of the patient: therefore, the need for high spatial resolution must be conciliated with rapid arterial-phase imaging, and the acquisition cannot be longer than artery–vein re-circulation time in order to avoid the widespread overlap of venous structures. Representative clinical examples are the assessment of carotid, renal and peripheral arteries. This divergent demand for high temporal and spatial resolution still persists, imposing significant constraints on scan protocols.
The Blood-pool Concept
Conventional CAs have an intravascular half-life that can be estimated in the order of a few minutes. The only compound that weakly binds to serum albumin is gadolinium-enhanced benzyloxypropionictetra-acetate (Gd-BOPTA),7,8 which has been positively evaluated for parenchymal and vascular imaging compared with other conventional interstitial CAs. However, the vascular half-life of Gd-BOPTA is still shorter than required to perform long-lasting high-resolution acquisitions.
Recently, a new generation of CAs with intravascular distribution, also referred to as blood-pool agents, has become available: these compounds can persist in the vascular bed for a longer time period than conventional CAs, allowing the acquisition of CE-MRA sequences with exquisite spatial resolution, higher matrix values and smallest possible voxel size.
Gadofosveset trisodium (MS-325), commercial name Vasovist® (Bayer Schering Pharma AG), is the first intravascular CA approved for CEMRA in the EU. About 85% of the gadofosveset binds non-covalently to human plasma albumin, leading to a half-life of several hours and a primarily renal excretion, providing extended intravascular enhancement compared with existing conventional CAs. Moreover, the T1 relaxivity of Vasovist is approximately four to five times that of conventional extracellular CAs at 1.5T and up to 10 times higher at 0.5T. Intravenous injection of 0.03mmol/kg of Vasovist has been determined to be safe, well tolerated and effective in phase I and II clinical trials. In addition to conventional first-pass (FP) arterial-phase imaging, CE-MRA with Vasovist allows steady-state (SS) imaging to be performed: an equilibrium state in the contrast kinetics is reached about three minutes after administration and, due to the slow clearance of the CA from the blood, imaging is possible for up to one hour. The SS approach takes advantage of this long temporal window by adjusting imaging protocols with preparation pulses, smaller fields of view (FoV) and increased in-plane resolution with extra-thin 3D partitions. The use of SS theoretically overcomes the conflict between temporal and spatial resolution: fast acquisition is no longer mandatory and images with exquisite anatomical detail can be obtained virtually without any time limitation in almost every vascular territory.9–12
Clinical Applications of Vasovist-enhanced Magnetic Resonance Angiography
Head and Neck
For imaging of supra-aortic vessels, the acquisition strategies of FP imaging are very similar to those of conventional CE-MRA, using intermediate matrix (384x384) and millimetric slice thickness protocols with the shortest scan time (12 seconds); the flip angle should be adapted to an approximate value of 35°, which is optimal for obtaining the highest signal from blood. Due to the peculiar physics and kinetics of Vasovist, an excellent image quality can be obtained at FP with half the dosage and half to one-third the injection rate of a conventional CA, with the benefit of a higher signal-to-noise ratio (SNR).13
For SS imaging, the protocols should be adapted to perform a submillimetric isotropic acquisition: the matrix value can be raised to 896x896, with a slice thickness of 0.7/0.5mm, and the recommended voxel size can be reduced to 0.512/0.343mm3.14 If IPAT is used in combination with the peculiar physics and pharmacokinetics of the CA, high spatial resolution of SS may be achieved without a significant cutback in SNR and in a reasonable amount of time. Regarding diagnostic accuracy, CE-MRA with Vasovist has been demonstrated to be highly sensitive and specific for the detection of significant stenosis in the carotid territory: multiplanar reconstruction from isotropic data sets yields an incremental diagnostic value for the assessment of stenosis degree and plaque morphology (see Figure 1). Because of its intravascular persistence, Vasovist can also be used in the diagnosis and characterisation of vasculitis involving epiaortic vessels (see Figure 2), intracranial aneurysms and arterovenous malformations, as well as to demonstrate the vascular supply of brain tumours.13 The feasibility of functional brain MR imaging (MRI) with 3D gradient echo (GRE) T1-weighted sequences and Vasovist instead of highly T2*-weighted sequences has recently been demonstrated, potentially reducing the susceptibility-related artefacts associated with blood-oxygen-level-dependent (BOLD) functional MRI techniques.15
Heart
Whole-heart CE-MRA of the coronary arteries is a technically difficult task and is not part of routine clinical practice. Electrocardiogram (ECG)- and respiratory-gated 3D sequences represent the most promising solutions, but are time-consuming and require prolonged vascular enhancement. This technique has gained new momentum with the advent of blood-pool CAs. 3D GRE or 3D-balanced SSFP sequences with fat saturation and inversion pre-pulses can be used to perform whole-heart imaging with Vasovist. To determine the optimal individual inversion recovery pre-pulse delay for 3D balanced SSFP sequences, an inversion-prepared segmented T1 GRE cine sequence is performed before contrast-enhanced scan (Look-Locker technique); the heart phase at which the myocardial signal has the lowest signal intensity is then used as the pre-pulse delay for the whole-heart scan. IPAT may be adopted as it allows higher spatial resolution and shorter scan times.
Whole-heart coronary CE-MRA with Vasovist (see Figure 3) enables significant improvement in contrast-to-noise ratio (CNR), blood–myocardial contrast, image quality, visible vessel length and vessel sharpness over non-contrast MRA.16 Perfusion imaging based on blood-pool CAs has also been reported to successfully identify myocardial perfusion defects in an animal model.16 Further experience for whole-heart CE-MRA with Vasovist is expected in larger series of patients.
Aorta and Renal Arteries
FP imaging of the thoraco-abdominal aorta and its main branches may substantially benefit from the use of a blood-pool agent: fast acquisitions with increased spatial resolution can be performed with IPAT, achieving images with high SNR and CNR during a single breath-hold17 (see Figure 4). Moreover, the use of Vasovist can be combined with recently introduced advances in scan protocols, such as clever K-space segmentation techniques (time-resolved imaging of contrast kinetics [TRICKS], TWIST and CENTRA): these time-resolved approaches present the common feature of fast, repeated 3D acquisitions during a single breath-hold in the FP phase (see Figure 5).
In the renal territory, this technique can be used to acquire multiple vascular phases (ranging from the pure arterial to the venous phase), not only allowing selection of the phase that is most suited for the purpose of diagnosis, but also enabling the evaluation of quantitative parameters such as time to peak, transit time and maximal signal intensity, which can be used to acquire information on reno-vascular functionality. However, in the thoracic and abdominal territories, cardiac and breathing motion artefacts pose considerable problems for the optimisation of SS protocols: the acquisition time is limited to the time-frame of a single breath-hold, thus the potential of the intravascular CA to facilitate high spatial resolution cannot be fully exploited.18,19 To optimise image quality the SS protocol can be adapted: in the thorax, temporal resolution may be improved by acquiring two sagittal slabs covering the aorta, pulmonary arteries and both lungs.
Similar adjustments can be made in the abdomen, acquiring two oblique coronal slabs along the course of the renal arteries and increasing the IPAT acceleration factor. In addition, advanced acquisition techniques involving free-breathing navigator approaches and ECG gating could be effective for the SS imaging of both the thoracic and the abdominal vasculature.
Peripheral Vessels
CE-MRA represents a real technological revolution in the study of the peripheral arterial tree: it yields images with good spatial and contrast resolution, providing valid information on the degree, area and extension of steno-obstructive pathology. Its diagnostic accuracy reaches sensitivity and specificity of 90–100% when evaluating the iliac and femoral territory.20 Collateral circles of compensation can be easily located, and using time-resolved imaging techniques it is possible to evaluate the velocity of flow, particularly in the presence of vascular obstructions or an evident difference in the speed of the flow between the two limbs. However, the diagnostic accuracy of CE-MRA is significantly reduced in the arterial districts distal to the popliteal artery, an area where vessels are very small, collaterals are hardly recognisable and stenoses may be very difficult to diagnose. In this territory, decisive factors are represented by the size of the voxel, the quantity and velocity of the injection of the CA and the method of acquisition of the K-space. Despite the sophisticated options available, establishing the exact delay when scanning the calf arteries can be more complicated than for other districts, often due to haemodynamic alterations and differences between the two legs. Delayed acquisition may determine the overlapping of the venous structures with poor vascular enhancement, while an anticipated acquisition may miss the peak of the arterial circulation phase, leading to suboptimal visualisation of the vascular lumen.
Such problems can be avoided by using Vasovist: by coupling a conventional FP acquisition (see Figure 6) to high-resolution SS imaging, it is possible to eliminate acquisitions with low enhancement or poor artery–vein discrimination. On SS images, although small-calibre arterial and venous structures run in close vicinity, the vessels can be clearly differentiated due to the extremely high spatial resolution, enabling excellent evaluation of wall alterations and stenosis19 (see Figure 7). When imaging the run-off vessels, the recommended voxel size of SS sequences should range between 0.7 and 0.5mm3 for a well-balanced compromise between SNR, spatial resolution and motion artefacts during lengthy acquisition (see Figure 8). Recent studies with Vasovist have shown that SS imaging can provide additional diagnostic information for the identification and characterisation of vessel stenosis in patients with peripheral arterial disease in comparison with CE-MRA with conventional CAs.
Another elegant application of CE-MRA with Vasovist is represented by the display of artero-venous malformations (see Figure 9) and soft-tissue tumours (see Figure 10): in these cases the use of time-resolved sequences yields information about the hyperkinetic circle following the direction of the flow, while SS imaging may provide additional diagnostic elements such as the evaluation of small arterial feeders or the presence of thrombi.21
Future Applications
CE-MRA with Vasovist and SS imaging represents a revolutionary application of non-invasive vascular imaging. However, as with all new imaging techniques, it remains under development and has yet to reach the state of the art. Protocol implementations such as experimental segmentation softwares22,23 and advanced K-space-sampling techniques24 have been suggested in order to manage the venous enhancement correctly in the SS phase and yield more accurate diagnostic information that can be interpreted more quickly in patients affected by steno-occlusive arterial disease. However, many potential applications still wait to be explored: CE-MRA with Vasovist has been demonstrated to be effective in the visualisation of vessel inflammation in patients affected by vasculitis; moreover, it could be used for the dynamic imaging of arterovenous malformations and large musculoskeletal haemangiomas, as well as to demonstrate arterial feeders of hypervascular tumours.
Conclusions
Vasovist is the only currently approved CA among the recently manufactured blood-pool compounds. It has physical properties that are ideal for its use with CE-MRA, allowing both high-quality conventional FP imaging and SS acquisitions with extended spatial resolution. At present, the most interesting applications of Vasovist CE-MRA are represented by its use in the carotid, cardiac and peripheral territories; the acquisition of SS sequences in the thoraco-abdominal district is still restricted by the necessity for respiratory gating. Further studies on many other possible applications of CE-MRA with Vasovist are warranted.