Current Techniques Of Vascular Imaging
Approximately 10,000 people die each year from coronary heart disease, stroke and other circulatory diseases in Ireland (1). Therefore the identification of these diseases through vascular imaging is of utmost importance. Current methods in vascular imaging are conventional x-ray angiography and digital subtraction angiography (DSA) and computed tomography and magnet resonance angiography (CTA and MRA). For diagnostic purposes, MRA and especially CTA are the gold standard; for interventional purposes, DSA is considered the method of choice. (2)
However these methods methods are not without there respective pitfalls. DSA and CTA burden patients and physicians with a considerable amount of ionising radiation. Additionally both CTA and MRA overestimate vascular stenosis(3,4)and are limited in time resolved imaging, with MRA being limited in temporal resolution and CTA due to restrictions related to radiation protection. In the case of DSA, it only two-dimensional images and does not allow exact quantification of pathologies like stenosis. MPI can overcome most of these limitations. MPI’s high temporal and spatial resolution meets the requirements of cardiovascular, neurologic, and peripheral vascular applications. Current techniques involve the use of magnetic tracer materials such as ferucarbotran that can be administered intravenously, and the tracer material is distributed in the vascular system for a limited amount of time, until it accumulates in the reticuloendothelial system. Here, the particles are disintegrated, and the iron is transferred into the normal iron metabolism of the body. Thus, there seem to be no lifetime limit on how much tracer can be administered to a patient.
These agents, combined with the ultrafast imaging capabilities of MPI, are well suited for first-pass measurements, including dynamic angiography of the heart and the large vessels as well as cerebral and myocardial perfusion studies. (2)Compared with currently available techniques for the measurement of tissue perfusion, including nuclear techniques, MRI, CT, and ultrasounds some of which are mentioned above, MPI offers several important advantages. MPI has a the lack of ionising radiation compared with SPECT, PET, and CT. This allows for repetitive and follow-up measurements. Due to the relation between the tracer concentration and the MPI signal being linear, the technique allows for noninvasive quantitative measurements of tissue perfusion given as millilitre of blood per gram of tissue. The extremely fast data acquisition capabilities provide coverage of the entire heart or the entire brain with high temporal resolution. Furthermore, quantitative functional flow measurements can easily be combined with structural information, given by noninvasive angiography with sub-millimetre resolution.
For example, a cardiac MPI measurement lasting less than a minute may provide high-resolution noninvasive coronary angiography combined with quantitative perfusion measurements for the assessment of myocardial ischemia. (5)When compared to MRI, MPI presents with a significant advantage, the breath hold sequences required are substantially shorter are so negligible that they are not required. This is due to the ability of MPI to assess a whole organ three-dimensionally with such a high temporal resolution. The fast 3-dimensional imaging capabilities combined with specially coated instruments can be used for image-guided interventions. In this setting an intravenous injection of tracer material can be used to visualise the vessels in 3 dimensions. Together with the visualisation and tracking of the instruments, this would allow an MPI-based interventional navigation in a 3-dimensional image-guided scenario without ionising radiation. This application will be beneficial for vascular (eg, in coronary heart or peripheral arterial disease) as well as electro-physiologic interventions. Several studies have been conducted in relation to this. (2,5) In 2009 Weizenecker et al. the first in vivo 3D real-time MPI scans are presented revealing details of a beating mouse heart using a clinically approved concentration of a commercially available MRI contrast agent. 18 exams were performed with two representative results have been selected for presentation. According to Weizenecker et al. A temporal resolution of 21. 5 ms is achieved at a 3D field of view of 20. 4 × 12 × 16. 8 mm^3 with a spatial resolution sufficient to resolve all heart chambers.
However this has limitations as MPI morphological information can only be obtained of contrasted structures. (6)With an open or single-sided scanner geometry, MPI allows supreme patient access. In combination with the very good signal-to-noise-ratio(SNR), temporal and spatial resolution, a tracer with a good safety profile, and the absence of ionising radiation, MPI is an interesting option for vascular interventions as well. But as MPI is only visualising the SPIONs, devices for vascular interventions need to be labeled for use in MPI. This can be achieved by loading the lumen with SPIONs, applying a SPION-based coating to the devices or even integrating SPIONs into the structure of the catheters. (7)Cellular and targeted imaging SPIONs are generally collected by the body’s reticuloendothelial system (RES). Larger SPIONs like Resovist are cleared very fast from the bloodstream by the RES in liver and spleen, which can be used for the detection of hepatocellular carcinoma, for example. Smaller SPIONs circulate longer, extravasate, and are then collected by the cells of the RES to accumulate in lymph nodes. This principle was used in lymph node staging of pelvic cancer.
Furthermore, the affinity of SPIONs toward cells of the RES has been used for inflammation imaging, eg. , in arthritis or even vulnerable atherosclerotic plaques. (11-13) SPIONs were used also for tumour imaging, utilising the enhanced permeability and retention effect of the tumour vessels or the defective blood–brain barrier in terms of passive targeting. (14) All these applications have in common that they rely on general characteristics of the SPIONs and “the underlying specific pathology”. In the setting of MPI, the use of SPIONs in combination with a handheld MPI probe, similar to ultrasound, for the detection of the sentinel lymph node in breast cancer diagnostics has been already proposed as a clinical application. (15) First studies explored the use of MPI to detect stem cells. (16,17) These cells can be loaded with up to 10 pg of iron, which should be within the theoretical and technical possible detection limit of MPI. Similarly, red blood cells can be loaded with iron oxide– based tracer materials, which would result in a blood pool contrast agent with extremely long blood retention times of up to 120 days,(18,19) which would support long procedures such as those performed today in the electrophysiology laboratory or the assessment of therapy response in oncology by revisiting a tumour to monitor its remission.
For more specific applications, SPIONs can be modified by different coatings and especially by adding ligands, such as antibodies, peptides, polysaccharides, and other molecules for active targeting so that the SPIONs only bind to specific cells. Another approach being taken is to label specific cells with SPIONs ex-vivo and monitor their behaviour in vivo, eg, their migration, by visualising the intracellular SPIONs (cellular imaging). Both approaches are already being extensively researched for many disease entities. The detection of tumours are the most prevalent application, but others such as detection and monitoring of inflammation, cardiovascular disease, apoptosis, transplant rejection reactions, or neurodegenerative disorders are also being investigated. Recently Ittrich et al. summarised these applications. (20) Most of these approaches are, in principle, designed for SPION-based in vivo MR imaging. Sensitivity for SPION detection in MPI exceeds that in MRI, as MPI visualises SPIONs directly by detecting the particle signal, which is 22×106 times stronger than the proton’s magnetisation in MRI. Saritas et al. describe a detection limit for their current MPI scanner system of about 500 stem cells when labelled with Resovist; due to further development in scanner and SPION technology they see “potential for orders-of-magnitude improvement. ”(21) In contrast in another study Bulte et al. set detection limit of Resovist labeled mesenchymal stem cells below 100 cells. (22) Again, due to further development especially in the field of MPI-dedicated SPIONs, this number will improve. These data show the potential of MPI for cellular and targeted imaging in vivo due to its sensitivity. When very high temporal resolution is not necessary, as most often is the case in targeted/cellular imaging, it can be traded in for further enhancing MPI sensitivity. Nevertheless, MPI is not as sensitive as nuclear imaging. However, the main advantages of MPI are that there is no ionising radiation involved and that the shelf life of SPIONs is by orders of magnitudes longer than that of radionuclides, which will improve handling, work flow, and lower costs.
Moreover, production costs of SPIONs are less than those of radionuclides in the first place. In terms of cellular imaging, the internalisation of Resovist in red blood cells for a substantially prolonged blood circulation time and MPI contrast could already be demonstrated as an example for in vivo cellular imaging in MPI. (23)Application of this device in The SPION will be the key part for the success of MPI as a method. With new biocompatible particles that are optimised for use in MPI, the system’s performance will increase dramatically, especially in terms of spatial resolution and sensitivity. With that in mind and besides clinical applications like vascular imaging and interventions, MPI has the potential to pick up SPION-based concepts for cellular and targeted imaging to enable their translation into clinical imaging. The proven bio-compatibility of SPION will enable MPI to skip many hurdles on its journey to enter a clinical setting as it has been used in treatments already such as pelvic cancer as highlighted above. The use of SPIONs to label head and neck squamous cell carcinoma cells for visualisation of their migration has recently been proposed. (24) First experiments toward using MPI as a tool for theranostics have been published;(25,26) functional MPI tracers have already been described as well. (27)Until now, most of these scenarios still need to be assessed in vivo. A big step toward standardised in vivo MPI research has been made by the development of the first commercially available MPI scanner for small animals. Currently, two of those systems are being installed at German Universities in Hamburg and Berlin. (28) Many working groups are engaged in development of dedicated SPIONs for MPI with promising results, another very important step to improve MPI. Additionally cerebrovascular applications have been hypothesised as a potential application. Perfusion imaging in diagnosis of ischemia, in particular, is still suboptimal and requires CT-perfusion scans with high doses of ionising radiation.
Furthermore, patients with intracranial hemorrhage, especially subarachnoid hemorrhage after rupture of an intracranial aneurysm, often develop spasms of the intracranial arteries, which can lead to serious brain infarction. The diagnosis of intracranial arterial spasms using Doppler ultrasound is difficult. DSA is still gold standard but always requires an interventional procedure and, as well as the alternative perfusion CT, is socialised with high and repeated doses of ionising radiation. Here, perfusion MPI could be a valuable addition. In a scenario with a single- sided scanner geometry that is integrated in the headboard of the bed and blood pool tracers, it might even be possible to monitor the brain perfusion permanently.
