Coronary heart disease is the number one cause of death in western societies. A rapid and noninvasive method of early detection would be important for the timely institution of therapy. Several noninvasive methods have been applied but none has provided reliable detection of underperfused myocardium with good resolution. MRI imaging is a noninvasive technique that has several possible advantages over other existing methods, i.e., electrocardiographic and radionuclide. MRI's main advantage is its excellent soft tissue resolution. For coronary heart disease, however, it is hampered by the lack of sufficient contrast between underperfused and well-perfused myocardium. Combined with functionally specific contrast agents, MRI would nevertheless have the potential to enable the early detection of abnormalities in myocardial perfusion and of damaged myocardium. These agents affect the contrast of water proton T1, or T2, thus effecting functional enhancement of contrast in MRI images. Existing agents, however, are not specific enough nor are retained long enough in the myocardium to allow stress-coupled MRI of perfusion. For several years our central goal has been the development of clinically applicable paramagnetic contrast agents for MRI detection of regional myocardial underperfusion and of ischemically damaged myocardium. Our research was focused around the development of agents that would be preferentially retained in the myocardium in proportion to perfusion. A systematic approach was followed based on the anticipated chemical, transport and magnetic properties of certain complexes of paramagnetic metals, in particular of gadolinium. Guided by the optimization of these properties, synthesis of new ligands for gadolinium were carried out and bifunctional, metal-binding, lipophilic fatty acid derivatives have been found the most promising. Magnetic and chemical properties of these agents have been tested in vitro, and in vivo in the ferret and dog model, and we have demonstrated that Gd(MHE-DTTA) in particular has sufficient water solubility, induces substantial MRI signal enhancement at relatively low dose, and remains effective for up to two hours without deleterious physiologic effects. We have also shown that this family of agents creates detectable MRI contrast of underperfused myocardium in images of LAD- occluded ferrets and dogs, in vivo. The goal of the present proposal is the systematic study of Gd(MHE-DTTA) efficacy and lack of harm in the in vivo experimental dog model of acute myocardial ischemia followed by reperfusion, with and without dobutamine-induced pharmacologic stress. These studies should enable the establishment of the clinical potential of this agent for early diagnosis of myocardial ischemic disease.
| Simor, Tamas; Gaszner, Balazs; Oshinski, John N et al. (2005) Gd(ABE-DTTA)-enhanced cardiac MRI for the diagnosis of ischemic events in the heart. J Magn Reson Imaging 21:536-45 |
| Saab-Ismail, N H; Simor, T; Gaszner, B et al. (1999) Synthesis and in vivo evaluation of new contrast agents for cardiac MRI. J Med Chem 42:2852-61 |
