University of Heidelberg
Department of Cardiology
A multitude of techniques have been developed for the noninvasive imaging of molecular alterations of the cardiovascular system. These techniques essentially utilise all cardiac imaging modalities, including radionuclide imaging, X-ray computed tomography (CT), thermography, ultrasound imaging and magnetic resonance imaging (MRI). However, only the two latter imaging modalities share the advantages of being noninvasive and without X-ray exposure for patients.
Site-specific targeted approaches with ultrasound
Molecular imaging with contrast-enhanced ultrasound imaging is based upon the detection of microbubble-based contrast agents. When these microbubbles are subjected to an acoustic impulse, the pressure wave causes the bubbles to undergo volumetric oscillations. These oscillations make them highly detectable by the imaging system. For the purpose of in vivo stability most ultrasound contrast agents consist of albumin or lipid shells, which contain inert high-molecular-weight gases, less soluble than air. Although microbubbles have been used for the majority of the molecular imaging applications,(1) other contrast agents have also been studied, including acoustically active liposomes, nanoscale emulsions and microtubules.(2) Because microbubbles are pure intravascular agents, microbubble-based agents designed for molecular imaging have been targeted to antigens expressed within the vascular compartment, such as endothelial cell receptors, or to blood cell proteins such as fibrin.(1) Targeted microbubbles have been designed by attaching disease-specific ligands such as monoclonal antibodies and peptides to the microbubble shell surface.
This strategy has utilised either covalent linkage or biotin/avidin link of ligand to lipid-shelled microbubbles. Targeted ultrasound contrast agents accumulate within regions of a specific disease process, where they can be detected during ultrasound imaging. This way, targeted imaging using ultrasound has been shown to provide valuable information on angiogenesis (integrin-targeted microbubbles) and on inflammatory processes (imaging of cardiac allograft rejection using intercellular adhesion molecule 1-targeted microbubbles), and has been demonstrated to detect intravascular or intracardiac thrombi (fibrin or platelets targeted contrast agents). Given the broad spectrum of potential clinical applications, such as imaging of angiogenesis, atherosclerosis and vascular thrombosis, targeted ultrasound imaging may provide a versatile adjunct for better defining pathologies in several medical and surgical situations. Furthermore, ultrasound imaging also has the advantage of being relatively inexpensive and portable, and it uses a technology that is already in widespread use in clinical routine.
Molecular imaging using MRI
MRI is a particularly attractive method for molecular imaging applications. This is due to its noninvasive nature and its ability to image any tomographic plane through a three-dimensional volume with high spatial resolution. MRI provides high contrast-to-noise ratios between tissues of interest within reasonable imaging times. Molecular imaging with MRI is based upon the local changes in T1-, T2- and T2*-relaxation rates of the tissue caused by the contrast agents.(3) Examples of target molecules are surface phospholipids, which are expressed on apoptotic cells and adhesion molecules, such as vascular-cell-adhesion-molecule 1, P-selectin and E-selectin.(4) Such molecules are expressed in high density on endothelial cells in areas of atherosclerotic plaque. Furthermore, MRI has been shown to detect human thrombi, using gadolinium-loaded, lipid-encapsulated perfluorocarbon nanoparticles, which are targeted against fibrin. Further experimental studies have also used superparamagnetic nanoparticles as imaging agents in order to detect early atherosclerotic changes, by exploiting T2- and T2*-shortening effects of these particles.(5) These nanoparticles are engulfed by inflammatory active macrophages, within atherosclerotic lesions, or in areas of inflamed myocardium, and create local magnetic susceptibility artifacts, which can be visualised as signal voids on T1- and on T2*-weighted MR images. However, signal loss may also arise from many other sources, such as motion or absence of tissue, as well as from anatomical structures within plaques, such as the “fibrous cap” and calcifications. All these factors reduce the specificity of such approaches to detect the “vulnerable plaque”.
To overcome these limitations, spectrally selective MRI pulse sequences have recently been introduced, which can selectively detect magnetic susceptibility artifacts in areas of superparamagretic nanoparticles as positive signal, and simultaneously suppress surrounding tissue.(6) Initial experiments with these “positive contrast” MR sequences in an atherosclerotic rabbit model have demonstrated that high spatial resolution MRI, can successfully visualise the accumulation of superparamagnetic nanoparticles in atherosclerotic plaque with high accuracy.(7)
Furthermore, targeted superparamagnetic nanoparticles, conjugated with Arg-Gly-Asp (RGD) peptides, have recently been shown to specifically label alpha(v)beta(3) integrins, which are expressed on endothelial cells.(8) Such innovative approaches may further enhance the specificity of molecular imaging approaches with MRI. Potential clinical applications of targeted cardiovascular imaging with MRI include the noninvasive detection and localisation of thrombus and the detection of macrophage-dense, “vulnerable” plaque in patients with acute coronary syndromes and stroke.
Thus, molecular MRI is likely to continue to grow in importance in the future and will strongly complement the central role of MRI in conventional anatomical imaging. If ultimately successful, molecular MRI will allow early recognition of pathology, prompting therapeutic intervention before the progression of cardiovascular pathologies.
- Behm CZ, et al. Ultrasound Q 2006;22:67-72.
- Korosoglou G, et al. Ultrasound Med Biol 2006;32:1473-8.
- Sosnovik DE, et al. Curr Opin Biotechnol 2007;18:4-10.
- Nahrendorf M, et al. Circulation 2006;114:1504-11.
- Ruehm SG, et al. Circulation 2001;103:415-22.
- Korosoglou G, et al. A new method to visualize vessels: off-resonance angiography. Phantom and rabbit studies. Berlin: ISMRM; 2007.
- Korosoglou G et al, AHA, Orlando; 2007.
- Zhang C, et al. Cancer Res 2007;67:1555-62.