Edward C. Parsons

In Vivo Molecular Imaging of Acute and Subacute Thrombosis Using a Fibrin-Binding Magnetic Resonance Imaging Contrast Agent

Background—Plaque rupture with subsequent thrombosis is recognized as the underlying pathophysiology of most acute coronary syndromes and stroke. Thus, direct thrombus visualization may be beneficial for both diagnosis and guidance of therapy. We sought to test the feasibility of direct imaging of acute and subacute thrombosis using MRI together with a novel fibrin-binding gadolinium-labeled peptide, EP-1873, in an experimental animal model of plaque rupture and thrombosis. Methods and Results—Fifteen male New Zealand White rabbits (weight, ≈3.5 kg) were made atherosclerotic by feeding a high-cholesterol diet after endothelial aortic injury. Plaque rupture was then induced with the use of Russell’s viper venom (RVV) and histamine. Subsequently, MRI of the subrenal aorta was performed before RVV, after RVV, and after EP-1873. Histology was performed on regions suggested by MRI to contain thrombus. Nine rabbits (60%) developed plaque rupture and thrombus, including 25 thrombi visually apparent on MRI as “hot spots” after injection of EP-1873. Histological correlation confirmed all 25 thrombi (100%), with no thrombi seen in the other regions of the aorta. In the remaining 6 rabbits (control) without plaque rupture, no thrombus was observed on the MR images or on histology. Conclusions—We demonstrate the feasibility of in vivo “molecular” MRI for the detection of acute and subacute thrombosis using a novel fibrin-binding MRI contrast agent in an animal model of atherosclerosis and acute/subacute thrombosis. Potential clinical applications include thrombus detection in acute coronary syndromes and stroke.

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

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 (n=6). After successful demonstration, in-stent coronary thrombosis was induced by x-ray–guided placement of thrombogenic-coated, MR-lucent stents (n=5). After stent placement, 60 &mgr;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 (≈250 &mgr;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 &mgr;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.

Molecular Magnetic Resonance Imaging of Coronary Thrombosis and Pulmonary Emboli With a Novel Fibrin-Targeted Contrast Agent

Background—The differential diagnosis of acute chest pain is challenging, especially in patients with normal ECG findings, and may include coronary thrombosis or pulmonary emboli. The aim of this study was to investigate the novel fibrin-specific contrast agent EP-2104R for molecular targeted MR imaging of coronary thrombosis and pulmonary emboli. Methods and Results—Fresh clots were engineered ex vivo from human blood and delivered in the lungs and coronary arteries of 7 swine. Subsequent molecular MR imaging was performed with a navigator-gated free-breathing and cardiac-triggered 3D inversion-recovery black-blood gradient-echo sequence before and after systemic administration of 7.5 &mgr;mol/kg EP-2104R. Two swine served as the control group. MR images were analyzed by 2 investigators, and contrast-to-noise ratio and gadolinium concentration in the clots were assessed. Before contrast media application, no thrombi were visible. After contrast administration, all 32 pulmonary emboli, 3 emboli in the right heart, and 5 coronary thrombi were selectively visualized as white spots with a mean contrast-to-noise ratio of 32±19. The average gadolinium concentration from all 3 types of thrombi was 144±79 &mgr;mol/L. Conclusions—Molecular MR imaging with the fibrin-targeted contrast-agent EP-2104R allows selective visualization of acute coronary, cardiac, and pulmonary thrombi.

Thrombus imaging with fibrin-specific gadolinium-based MR contrast agent EP-2104R: results of a phase II clinical study of feasibility.

Purpose:To determine the feasibility of detecting thrombi using a fibrin-specific gadolinium-based magnetic resonance imaging contrast agent, EP-2104R. Methods:Subjects with confirmed thrombus in the venous system (n = 14), or in the heart, or arterial system (n = 38) were enrolled. Patients were imaged before and at various times following a 4 μmol/kg intravenous bolus injection of EP-2104R: <1 hour (N = 16), 2 to 6 hours (N = 36), and/or 20 to 36 hours (N = 33). Images were assessed by investigators at each site and by a single reader not affiliated with the sites to determine whether thrombi were visible, not visible, or further enhanced with EP-2104R. A subset of data was analyzed quantitatively by measuring a signal intensity relative to background tissue. Results:Overall, 29 thrombi were visible before contrast administration, 3 of 14 in the venous system, and 26 of 38 in the arteries and heart. Thrombi generally enhanced in signal after EP-2104R injection, and an additional 7 were visualized. After contrast, 4 of 14 thrombi were visible in the venous system, and 32 of 38 in the arteries and heart. Thrombi were more conspicuous when imaged at 2 to 6 hours post EP-2104R compared with within 1 hour, because of lower blood background. Quantitatively, the post: pre signal intensity ratio was 1.90 at 2 to 6 hours post injection (standard deviation = 1.08, N = 20, P < 0.001); and 2.04 (standard deviation = 1.29, N = 19, P < 0.0025) for the 20 to 36 hours time point. There were no serious adverse events considered related to study drug. Conclusion:EP-2104R enhanced magnetic resonance imaging detects thrombi not readily visible in precontrast screening and gives additional enhancement of thrombi that are visible in precontrast imaging.

Molecular magnetic resonance imaging of atrial clots in a swine model.

Background—The detection and differentiation of intracardiac masses is still challenging and may include neoplasms and thrombi. The aim of this study was the investigation of a targeted, fibrin-specific contrast agent (EP-2104R) for molecular targeted magnetic resonance imaging (MRI) of left atrial clots. Methods and Results—Chronic human thrombi were surgically implanted in the left atrial appendage of 5 swine. Molecular MRI was performed with a navigator-gated, free-breathing, cardiac-triggered 3D inversion-recovery, black-blood, gradient-echo sequence before and after systemic administration of 4 &mgr;mol/kg EP-2104R. MR images were analyzed by 2 investigators, and the contrast-to-noise ratio was calculated. Location of clots was confirmed by autopsy, and the gadolinium concentration in the clots was assessed. Before contrast agent administration, thrombi were not visible on black-blood MR images. After contrast administration, all atrial clots (n=5) were selectively visualized as white spots with a high contrast-to-noise ratio (clot/blood, 29.7±8.0). The gadolinium concentration in the clots averaged 74±45 &mgr;mol/L. Conclusions—The fibrin-specific MR contrast agent EP-2104R allows for selective and high-contrast visualization of left atrial clots by means of molecular targeted MRI.

Molecular MR imaging of human thrombi in a swine model of pulmonary embolism using a fibrin-specific contrast agent

Objective:Molecular targeted MR imaging of human clots material in a model of pulmonary embolism using a fibrin-specific magnetic resonance imaging contrast agent (EP-2104R, EPIX Pharmaceuticals, Cambridge, MA). Material and Methods:Fresh ex vivo engineered thrombi (human blood) and human clots removed from patients were delivered in 11 swine. Molecular MR imaging with a 3D gradient-echo [3D fast field echo (3DFFE)] sequence and a navigator-gated and cardiac-triggered 3D inversion-recovery black-blood gradient-echo sequence (IR) was performed before thrombus delivery, after thrombus delivery but before contrast media application, and 2 hours after i.v. administration of 4 &mgr;mol/kg EP-2104R. MR images were analyzed by 2 investigators and contrast-to-noise ratio (CNR) was assessed. Thrombi were removed for assessment of gadolinium (Gd) concentration. Results:Only after contrast media application were pulmonary emboli [freshly engineered thrombi (n = 23) and human clot material removed from patients (n = 25)] visualized as white foci on MR images. CNR was 13 ± 3 (ex vivo engineered clot) and 22 ± 9 (patient clot material) for the fast field echo (FFE)-sequence and 29 ± 9 (ex vivo engineered clot) and 43 ± 18 (patient clot material) for the IR-sequence, respectively. A high Gd concentration in the clots was found (82 ± 43 &mgr;M for the freshly engineered and 247 ± 44 &mgr;M for the clots removed from patients, respectively). Conclusions:EP-2104R allows for molecular MR imaging of human clot material in the pulmonary vessels of a swine model.

Molecular MRI of Cerebral Venous Sinus Thrombosis Using a New Fibrin-Specific MR Contrast Agent

Background and Purpose— Imaging of cerebral vein thrombosis is still challenging. Currently, diagnosis is based on CT venography and MRI including MRA and conventional digital subtraction angiography. However, especially in chronic cases, each method has shown its limitations. Newer strategies for MRI are found on molecular imaging using targeted contrast agents. The aim of this study was to prove the feasibility of a novel fibrin-targeted MR contrast agent (EP-2104R; EPIX Pharmaceuticals) for selective imaging of sinus venous thrombosis in an animal model. Methods— Thrombosis of the superior sagittal sinus with human blood was induced in 6 pigs using a combined microsurgical and interventional approach. MRI was then performed before and up to 120 minutes after injection of 4 &mgr;mol/kg body weight EP-2104R. Molecular imaging was performed with a 3-dimensional high-resolution T1-weighted gradient echo sequence. Time courses of signal-to-noise ratio and contrast-to-noise ratio were analyzed. Thrombi were then surgically removed and the Gadolinium concentration was assessed. Results— In all cases the thrombosis could be successfully induced; the complete MR protocol could be performed in 5 animals. In these cases the thrombi showed selective enhancement after injection of the molecular contrast agent. However, a continuous contrast-to-noise ratio increase was seen up to 120 minutes after contrast administration, achieving a contrast-to-noise ratio of 14.2±0.7 between clot and the blood pool. Conclusion— The novel fibrin-targeted molecular MR contrast EP-2104R allows selective and high-contrast imaging of cerebral sinus vein thrombosis in an animal model.

Safety and Efficacy of Gadofosveset­ Enhanced MR Angiography for Evaluation of Pedal Arterial Disease: Multicenter Comparative Phase 3 Study

OBJECTIVE The purpose of this study was to evaluate the safety and efficacy of gadofosveset, a gadolinium-based albumin-binding MRI contrast agent, in patients with pedal arterial disease. SUBJECTS AND METHODS A total of 185 adult patients with known or suspected pedal arterial disease were randomized in a group receiving 0.03 mmol/kg and a group receiving 0.05 mmol/kg of gadofosveset for MR angiography of the pedal arteries. Gadofosveset-enhanced and unenhanced time-of-flight MR angiograms were compared with conventional angiograms, the standard of reference, for the presence of vascular stenosis. All patients underwent drug safety analysis. RESULTS For each of three blinded readers, the specificity (21-35%) of gadofosveset-enhanced MR angiography was a statistically significant (p < 0.010) improvement over that of unenhanced MR angiography in the detection of clinically significant (> 50%) stenosis. The sensitivities of the two techniques were similar. For all blinded readers of MR angiograms, sensitivity, specificity, and accuracy were higher with use of the 0.03-mmol/kg dose of gadofosveset than with the 0.05-mmol/kg dose. In the 0.03-mmol/kg group, 28% of patients reported a total of 50 adverse events, 96% of which were reported as mild or moderate. In the 0.05-mmol/kg group, 28% of patients reported a total of 55 adverse events, 98% of which were reported as mild or moderate. No patients died; one patient left the study because of myocardial infarction considered unrelated to the study drug. CONCLUSION Because of markedly better efficacy than no contrast agent and a minimal and transient side-effect profile, 0.03 mmol/kg of gadofosveset was found safe and effective for MR angiography of patients with pedal arterial disease.

High spatial resolution magnetic resonance imaging of experimental cerebral venous thrombosis with a blood pool contrast agent

PURPOSE The purpose of this study was to investigate the feasibility of clot visualization in small sinus and cortical veins with contrast enhanced MRA in a cerebral venous thrombosis animal model using a blood pool contrast agent, Gadofosveset, and high spatial resolution imaging. MATERIAL AND METHODS For induction of cerebral venous thrombosis a recently developed combined interventional and microsurgical model was used. Cerebral sinus and cortical vein thrombosis was induced in six pigs. Two further pigs died during the procedure. Standard structural, time-of-flight- and phase contrast-angiograms were followed by fast time resolved high resolution 3D MRA (4D MRA) and subsequent high spatial resolution 3D MRA in the equilibrium phase with and without addition of parallel imaging. Visualization of the clots using the different sequences was subjectively compared and contrast-to-noise ratio (CNR) was assessed. RESULTS In the remaining six animals the procedure and MR-imaging protocol including administration of Gadofosveset was successfully completed. The 3D high resolution MRA in the equilibrium phase without the addition of parallel imaging was superior to all the other applied MR measurement techniques in terms of visualization of the clots. Only applying this sequence bridging vein thromboses were also seen as a small filling defect with a high CNR of >18. CONCLUSION Only the non-accelerated high spatial resolution 3D MRA in the equilibrium in conjunction with the blood pool agent Gadofosveset allows for high-contrast visualization of very small clots in the cerebral sinus and cortical veins. STATEMENT CLINICAL IMPACT: Detection of cortical vein thrombosis is of high clinical impact. Conventional MRI sequences often fail to visualize the clot. We could demonstrate that, in contrast to conventional sequences, with high spatial resolution 3D MRA in the equilibrium in conjunction with the blood pool agent Gadofosveset very small clots in the cerebral sinus and cortical veins could be successfully visualized. We think that with the presented approach cortical vein thrombosis might also be sufficiently visualized in patients.