Biomedical subjects

Andrea J Wiethoff

Publications and source records attributed to Andrea J Wiethoff.

8 recordsLinked to original sources

PubMed2006

Initial imaging recommendations for Vasovist angiography.

Vasovist is a newly developed blood pool contrast agent for MR angiogiography (MRA). It consists of a low molecular weight molecule, chelated to Gadolinium, that strongly binds to plasma proteins, thus increasing its relaxivity and retention time in the vascular system. Due to its high efficiency, a smaller dose compared to existing Extracellular Fluid Contrast Agents is sufficient for diagnostic purposes, resulting in a lower injection volume. With appropriate adjustments of standard extracellular contrast injection protocols, a dynamic phase MRA can be achieved using routine MRA parameters. For extended phase imaging, ('steady-state') starting approximately 3 to 5 min post injection, repetition time (TR) and flip angle may be adjusted for optimization of intravascular signal. Preliminary technical recommendations for the optimization of contrast-enhanced MRA with Vasovist can be deducted from current clinical trial experience in various vessel beds.

Contrast Media↗

PubMed2005

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 micromol/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 micromol/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.

Animals↗

PubMed2005

Molecular magnetic resonance imaging of pulmonary emboli with a fibrin-specific contrast agent.

RATIONALE AND OBJECTIVES: The detection of pulmonary embolism is still challenging due to the often nonspecific clinical findings. The aim of this study was to investigate the potential of molecular targeted magnetic resonance imaging (MRI) of pulmonary emboli using low-dose application of a fibrin-specific contrast agent (EP-2104R; Epix Pharmaceuticals, Cambridge, MA). METHODS: Fresh clots from human blood were engineered ex vivo and delivered in the lungs of 11 swine. Subsequently, a T1-weighted breath-hold three-dimensional gradient-echo sequence was performed before as well as 5 minutes, 1 hour, and 2 hours after systemic administration of 7.5 (n = 5) or 4 (n = 5) micromol/kg EP-2104R. One swine that did not receive any contrast agent served as a control. MR images were analyzed by two investigators and contrast-to-noise ratio between the thrombus and the surrounding tissue (blood pool and lung parenchyma) was assessed. Localization of thrombi was compared with 16-row multislice computed tomography. Finally, the animals were killed and thrombi were removed for assessment of gadolinium concentration. MAIN RESULTS: Before contrast media application, thrombi were not visible on MR images. At 1 and 2 hours after contrast media injection, pulmonary emboli were selectively visualized with high-signal intensity foci, independent of the dosage used. A high gadolinium concentration in thrombi was found after both dosages (83 +/- 41 microM for 4 micromol/kg and 130 +/- 57microM for 7.5 micromol/kg), resulting in a similar high contrast-to-noise ratio on MR images (between 11 and 13). CONCLUSION: Systemic low-dose application of EP-2104R allows for selective molecular MRI of fresh pulmonary thromboembolism in a swine model.

Animals↗

PubMed2005

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 micromol/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 micromol/L. CONCLUSIONS: Molecular MR imaging with the fibrin-targeted contrast-agent EP-2104R allows selective visualization of acute coronary, cardiac, and pulmonary thrombi.

Angiography↗

PubMed2004

Synthesis and evaluation of a high relaxivity manganese(II)-based MRI contrast agent.

The manganese(II) ion has many favorable properties that lead to its potential use as an MRI contrast agent: high spin number, long electronic relaxation time, labile water exchange. The present work describes the design, synthesis, and evaluation of a novel Mn(II) complex (MnL1) based on EDTA and also contains a moiety that noncovalently binds the complex to serum albumin, the same moiety used in the gadolinium based contrast agent MS-325. Ultrafiltration albumin binding measurements (0.1 mM, pH 7.4, 37 degrees C) indicated that the complex binds well to plasma proteins (rabbit: 96 +/- 2% bound, human: 93 +/- 2% bound), and most likely to serum albumin (rabbit: 89 +/- 2% bound, human 98 +/- 2% bound). Observed relaxivities (+/- 5%) of the complex were measured (20 MHz, 37 degrees C, 0.1 mM, pH 7.4) in HEPES buffer (r(1) = 5.8 mM(-)(1) s(-)(1)), rabbit plasma (r(1) = 51 mM(-)(1) s(-)(1)), human plasma (r(1) = 46 mM(-)(1) s(-)(1)), 4.5% rabbit serum albumin (r(1) = 47 mM(-)(1) s(-)(1)), and 4.5% human serum albumin (r(1) = 48 mM(-)(1) s(-)(1)). The water exchange rate was near optimal for an MRI contrast agent (k(298) = 2.3 +/- 0.9 x 10(8) s(-)(1)). Variable temperature NMRD profiles indicated that the high relaxivity was due to slow tumbling of the albumin-bound complex and fast exchange of the inner sphere water. The concept of a high relaxivity Mn(II)-based contrast agent was validated by imaging at 1.5 T. In a rabbit model of carotid artery injury, MnL1 clearly delineated both arteries and veins while also distinguishing between healthy tissue and regions of vessel damage.

Animals↗

PubMed2004

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 micromol 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 (approximately 250 micromol/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 micromol/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.

Animals↗

PubMed2004

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, approximately 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.

Acute Disease↗

PubMed2003

Assessing the role of neutrophil apoptosis in the resolution of particle-induced pulmonary inflammation.

Following inflammatory-cell recruitment in the lung, neutrophil apoptosis and subsequent engulfment by macrophages are regarded as important components in the resolution of pulmonary inflammation. The goal of this study was to further investigate the role of apoptosis and its influence, if any, on the pulmonary inflammatory process following exposures to the following particulate types: amorphous (AMO) or crystalline silica (Si), lipopolysaccharide (LPS), or pigment-grade titanium dioxide (TiO2). Rats were intratracheally instilled either with TiO2, AMO, or Si particles at doses of 1 or 5 mg/kg or 6 microg LPS. Following exposures, bronchoalveolar lavage fluids and lung tissues were collected and evaluated at 12, 24, 48, or 168 h (i.e., 1 wk). At the 1 mg/kg dose, AMO instillation produced the highest pulmonary inflammatory response, concomitant with a rise in apoptotic cells that mirrored temporally the transient nature of the inflammatory response. At 5 mg/kg, amorphous silica and crystalline silica particles induced substantial pulmonary inflammation [approximately 50-60% neutrophils (PMNs)] at 12 h postexposure (pe). A fundamental difference between the two inflammatory patterns, however, was the subsequent reversibility of inflammation in the AMO-exposed rats at 168 h postexposure and the sustained inflammatory effect in the Si-exposed animals measured through 168 h pe (approximately 40% PMNs). Pulmonary apoptotic responses in AMO-exposed rats mirrored temporally and correlated with the time-course reduction of inflammatory responses, leading to resolution. In the Si-exposed rats, apoptotic levels remained elevated, concomitant with sustained inflammation measured through 168 h pe. High doses of TiO2 particles produced transient lung inflammation, but with low levels of apoptosis. In addition, instillation of LPS produced a transient inflammatory response which mirrored the time course of apoptosis levels and was resolved by 168 h pe. cDNA microarray methods demonstrated that gene expression was altered for several apoptosis-related genes in AMO-, Si-, and LPS-exposed animals at 24 h pe. The results of these studies demonstrate that, following exposures, the resolution of lung inflammation correlated temporally with apoptotic levels of neutrophils in AMO- and LPS-exposed rats. Alternatively, instillation of crystalline silica resulted in sustained pulmonary inflammation and measurable apoptosis at 1 wk postexposure, but the apoptotic cell processes were not effective in resolving the inflammatory response. The findings suggest that the coordination between the resolution of inflammation and inflammatory cell apoptosis in the lung is dependent on the particle-type and that other factors, such as particle cytotoxicity, may also be important.

Animals↗