Over the past decade, noninvasive techniques have been developed to image processes in the cardiovascular system at the molecular and cellular levels [13
]. These molecular imaging techniques have aimed to provide novel insights into the molecular pathophysiology of cardiovascular disease and to elucidate the impact of molecular events on whole-organ physiology. Among these techniques, molecular magnetic resonance imaging (MRI), discussed extensively in this review, has emerged as a powerful tool.
The advantages of MRI over nuclear-based molecular imaging techniques include its higher spatial resolution, its superior soft tissue contrast, and its ability to integrate molecular, anatomic, and physiologic imaging data [18
]. In addition, MRI provides a unique platform for imaging the microstructural architecture of the myocardium by imaging the diffusion of water [22
]. Microstructural MRI provides insights into myocardial function at a scale between molecular and whole-organ imaging and has the potential to bridge further the divide between molecular biology and clinical translation. Molecular MRI has a sensitivity in the micromolar to nanomolar range depending on the imaging platform used. This is significantly lower than the picomolar sensitivity of nuclear-based and fluorescence imaging agents.
Another challenge with molecular MRI is that typical imaging agents, although well suited for imaging targets on the cell surface, cannot rapidly penetrate an intact cell membrane. In addition, once in the intracellular space, nanoparticulate MRI agents frequently are trafficked nonspecifically into endosomes and lysosomes. Although significant progress is being made in the development of intracellular MRI agents, nuclear imaging techniques remain superior in this regard.
Two broad imaging agent platforms are used for molecular MRI in the myocardium. Small gadolinium chelates, used as extracellular MR contrast agents for more than a decade, are well suited for detecting highly expressed targets such as fibrin and collagen [2
]. These agents have detection thresholds in the micromolar range, which, although significantly superior to iodinated contrast agents, support only the detection of highly expressed targets. Novel gadolinium constructs have thus been developed to overcome this sensitivity limit including gadolinium-containing lipoproteins, liposomes, and micelles [1
]. These large gadolinium constructs have nanomolar sensitivity but more complex pharmacokinetics and therefore are generally not well suited to imaging of the myocardium.
Magnetic iron oxide nanoparticles (MNPs) constitute the second large class of molecular MRI agents [19
]. Their use as an MR platform is based on their ability to modulate the uniformity of a magnetic field. Because MNPs are superparamagnetic, they have high magnetic relaxivities, allowing for the detection of sparsely expressed targets in the nanomolar range. They also are small (<50 nm), can penetrate the capillary membrane, and remain inert in the interstitial space.
A variety of ligands can be conjugated to MNPs including fluorochromes, small molecules, peptides, and small proteins. Examples of such ligands include annexin for apoptosis imaging [14
] and a vascular cell adhesion molecule-1 (VCAM-1)-targeted peptide for imaging adhesion molecule expression on the vascular endothelium [10
Molecular MRI currently is playing a significant role in preclinical cardiovascular investigation. It has the potential for expansion to clinical investigation in the near future.
In the context of cell death, molecular MRI approaches have been developed to image cardiomyocyte apoptosis [15
], cardiomyocyte necrosis [20
], and the inflammatory response to cell death [12
]. Techniques for imaging autophagy are being actively pursued. Microstructural MRI of ischemic injury in the myocardium has been performed ex vivo in a wide variety of models [22
]. More recently, it has been performed in vivo in mice with ischemia-reperfusion injury. The application of these techniques in neonatal mice is more challenging but still feasible. Although significant technical challenges remain, as discussed later, molecular and microstructural MRI currently can provide valuable insights into the mechanism of cell death in the myocardium.