In Vivo Magnetic Resonance Imaging of Coronary Thrombosis Using a Fibrin-Binding Molecular Magnetic Resonance Contrast Agent

Abstract

Background-The advent of fibrin-binding molecular magnetic resonance (MR) contrast agents and advances in coronary MRI techniques offers the potential for direct imaging of coronary thrombosis. We tested the feasibility of this approach using a gadolinium (Gd)-based fibrin-binding contrast agent, EP-2104R (EPIX Medical Inc), in a swine model of coronary thrombus and in-stent thrombosis. Methods and Results-Ex vivo and in vivo sensitivity of coronary MR thrombus imaging was tested by use of intracoronarily delivered Gd-DTPA-labeled fibrinogen thrombi (nϭ6). After successful demonstration, in-stent coronary thrombosis was induced by x-ray-guided placement of thrombogenic-coated, MR-lucent stents (nϭ5). After stent placement, 60 mol of EP-2104R was injected via the left main coronary artery. Free-breathing, navigator-gated 3D coronary MR angiography and thrombus imaging were performed (1) before and after stent placement and (2) before and after EP-2104R. Thrombi were confirmed by x-ray angiography and autopsy. Fibrinogen thrombi: 5 of 6 intracoronarily delivered Gd-labeled fibrinogen clots (Ϸ250 mol/L Gd) were visible on MRI and subsequently confirmed by x-ray angiography. In-stent thrombi: in-stent thrombosis was observed in all stents after EP-2104R. Four of 5 thrombi were confirmed by x-ray angiography. Chemical analysis of 2 thrombi demonstrated 99 to 147 mol/L Gd. Conclusions-We demonstrate the feasibility of MRI of coronary thrombus and in-stent thrombosis using a novel fibrin-binding molecular MR contrast agent. Potential applications include detection of coronary in-stent thrombosis or thrombus burden in patients with acute coronary syndromes.

Metalloprobes: Synthesis, characterization, and potency of a novel gallium(III) complex in human epidermal carcinoma cells

“…The contribution of medicinal inorganic chemistry has gained momentum in the field of pharmaceutical research with the successful outcome of metallodrugs in various diseases, such as cis-platin for chemotherapy [1,2], ferrochloroquine analogues for drug-resistant P. falciparum strains in malaria [3][4][5], vanadium(IV) insulin enhancing agent (BMOV) [6], and gadolinium-coordinated contrast-agents for magnetic resonance imaging (MRI) [7,8].…”

Molecular Imaging in Cardiovascular Diseases

“…This specific molecular probe allowed selective demonstration of a coronary in-stent thrombus in an experimental animal subject ( • " Fig. 2) [35]. The applied dose of 4 -7.5 μmol/kg was significantly lower than the typical non-specific gadolinium-based MR contrast agent dose of 0.1 -0.2 mmol/kg.…”

“…This fibrin-specific molecular probe has been successfully tested on patients for the disclosure of fibrin-rich thrombi. EP-2104 consists of a short peptide (11 amino acids) bound to four DOTA chelates [35]. An additional approach to increasing the relaxivity of contrast agents is the utilization of substances that assemble complexes on their own.…”

“…It also has a key function in thrombus formation following plaque rupture. In various studies a fibrin-specific low-molecular probe has been successfully employed for imaging thrombi in the jugular vein, aorta, pulmonary arteries as well as in coronary arteries [35,36,50,51]. Compared to conventional compounds such as Gd-DTPA, the probe indicated high sensitivity for the detection of fibrin; this is explained by the high relaxivity of the specific molecular probe.…”

MRI of atherosclerosis: diagnosis and monitoring therapy

“…Already, USPIO's which are ingested by macrophages, have been used to identify macrophage activity, hence inflammation, in atherosclerotic plaque in in vivo animal models [71] as well as humans [72,73,74]. In addition, there has been excitement over the development of contrast agents that specifically target plaque components such as the lipid core, or intraplaque thrombus [75,76,77]. Finally, newer targeted contrast agents aimed at specific cell surface receptors or proteins will be developed which undoubtedly allow for earlier more sensitive detection of atherosclerotic plaque while also enhancing plaque imaging.…”