Increased neovascularization in advanced lipid-rich atherosclerotic lesions detected by gadofluorine-M-enhanced MRI: implications for plaque vulnerability.

BACKGROUND: Inflammation and neovascularization may play a significant role in atherosclerotic plaque progression and rupture. We evaluated gadofluorine-M-enhanced MRI for detection of plaque inflammation and neovascularization in an animal model of atherosclerosis. METHODS AND RESULTS: Sixteen rabbits with aortic plaque and 6 normal control rabbits underwent gadofluorine-M-enhanced MRI. Eight rabbits had advanced atherosclerotic lesions, whereas the remaining 8 had early lesions. Magnetic resonance atherosclerotic plaque enhancement was meticulously compared with plaque inflammation and neovessel density as assessed by histopathology. Advanced plaques and early atheroma were enhanced after gadofluorine-M injection. Control animals displayed no enhancement. After accounting for the within-animal correlation of observations, mean contrast-to-noise ratio was significantly higher in advanced plaques than compared with early atheroma (4.29+/-0.21 versus 3.00+/-0.32; P=0.004). Macrophage density was higher in advanced plaques in comparison to early atheroma (geometric mean=0.50 [95% CI, 0.19 to 1.03] versus 0.25 [0.07 to 0.42]; P=0.05). Furthermore, higher neovessel density was observed in advanced plaques (1.83 [95% CI, 1.51 to 2.21] versus 1.29 [0.99 to 1.69]; P=0.05). The plaque accumulation of gadofluorine-M correlated with increased neovessel density as shown by linear regression analysis (r=0.67; P<0.001). Confocal and fluorescence microscopy revealed colocalization of gadofluorine-M with plaque areas containing a high density of neovessels. CONCLUSIONS: Gadofluorine-M-enhanced MRI is effective for in vivo detection of atherosclerotic plaque inflammation and neovascularization in an animal model of atherosclerosis. These findings suggest that gadofluorine-M enhancement reflects the presence of high-risk plaque features believed to be associated with plaque rupture. Gadofluorine-M plaque enhancement may therefore provide functional assessment of atherosclerotic plaque in vivo.

Vascular enhancement in early dynamic liver MR imaging in an animal model: comparison of two injection regimen and two different doses Gd-EOB-DTPA (gadoxetic acid) with standard Gd-DTPA.

OBJECTIVES: To investigate the influence of 2 different doses and injection rates on the enhancement of liver vasculature in Gd-EOB-DTPA enhanced liver MRI compared with the standard dose Gd-DTPA. MATERIALS AND METHODS: This animal experimental study has been approved by the local authorities. In 5 pigs, a time-resolved T1w 3D GRE sequence, and in a second experiment, a single-slice turbo FLASH T1w sequence with 3 frames/s were started each with contrast agent application of Gd-EOB-DTPA and Gd-DTPA. Three sets with different doses were performed with an injection rate of 1 and 2 mL/s which are as follows: A, Standard dose: 25 [mu]mol Gd-EOB-DTPA/kg body-weight (bw); B, Double dose: 50 [mu]mol Gd-EOB-DTPA/kg bw; and C, Standard dose: 100 [mu]mol Gd-DTPA/kg bw. Signal intensities were measured in aorta, vena cava inferior, portal vein, and liver parenchyma, and time-signal-to-noise (SNR)-curves were generated. The increase in SNR from baseline and several perfusion parameters were calculated. Statistical significance was tested with the Wilcoxon rank test at a significance level of P = 0.05. RESULTS: Mean peak enhancement (SNR) in the aorta was not significantly different for set A, B, and C with the same injection rate. Mean peak enhancement in the aorta was significantly higher for set A at 1 mL/s than at 2 mL/s (159.1 vs. 144.4, P = 0.043). Mean peak enhancement in the PV, the vena cava inferior, and the liver parenchyma was significantly lower for set A compared with set B and set C, at both injection speeds. The full width at half max was significantly longer for injection protocols with 1 as compared with 2 mL/s for sets A and set B. Set A with 1 mL/s reached similar values as compared with set C with 2 mL/s for the full width at half max (8.92 vs. 9.40; P = 0.35), for the area-under-the curve (1736.64 vs. 1912.74; P = 0.69) and the maximal signal-to-noise ratio (25.21 vs. 25.37; P = 0.69). CONCLUSION: Despite the lower amount of gadolinium in the standard dose of Gd-EOB-DTPA, the results showed that the arterial enhancement in Gd-EOB-DTPA-enhanced dynamic liver MRI was comparable to Gd-DTPA. This result can be explained mainly by the higher relaxivity. Choosing a lower injection rate additionally supported to compensate for the lower injection volume by stretching the bolus without decreasing the peak. In this respect, an injection rate of 1 mL/s showed better results with regard to the arterial enhancement compared with 2 mL/s.

Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C.

OBJECTIVES: Assessment of the complex stability and Gd3+ dissociation rate of all marketed gadolinium-based MRI contrast agents (GBCA) in human serum at pH 7.4 and 37 degrees C. METHODS AND RESULTS: The kinetic profiles of Gd3+ dissociation of GBCAs were determined by incubation for 15 days in human serum from healthy volunteers at a concentration of 1 mmol/L, pH 7.4, and 37 degrees C. The initial rates of Gd3+ release and the amounts of Gd3+ released after 15 days were established by HPLC-ICP-MS analysis. In an attempt to simulate the situation in patients with end-stage renal disease who often have elevated serum phosphate levels, the influence of 10 mmol/L phosphate on Gd3+ dissociation was also investigated.The GBCAs were grouped and ranked in the following order according to their stabilities in native human serum at pH 7.4 and 37 degrees C [% Gd release after 15 days and initial rate (%/d) (95% confidence interval) in brackets]. NONIONIC LINEAR GBCAS: Optimark [21 (19-22) %, 0.44 (0.40-0.51) %/d) and Omniscan [20 (17-20) %, 0.16 (0.15-0.17) %/d]. IONIC LINEAR GBCAS: Magnevist [1.9 (1.2-2.0) %, 0.16 (0.12-0.36) %/d], Multihance [1.9 (1.3-2.1) %, 0.18 (0.13-0.38) %/d], Vasovist [1.8 (1.4-1.9) %, 0.12 (0.11-0.18) %/d], and Primovist [1.1 (0.76-1.2) %, 0.07 (0.05-0.08) %/d]. MACROCYCLIC GBCAS: Gadovist, Prohance, and Dotarem (all < limit of quantification of 0.1%, <0.007%/d).In the presence of additional 10 mmol/L phosphate in serum, the initial Gd release rates of the nonionic linear GBCAs, Omniscan, and Optimark increased about 100-fold, and, after 15 days, the amount of Gd3+ released from these agents was more than 75% higher than in native serum. The initial rates found for the ionic linear GBCAs increased about 12- to 30-fold, but, despite this, increase in the initial rate, the amount of Gd3+ released after 15 days was comparable to that in native serum. The elevated phosphate level did not lead to any measurable release of Gd3+ from the 3 macrocyclic GBCAs. CONCLUSIONS: The release of Gd from all linear Gd3+ complexes in human serum was several orders of magnitude greater than predicted by the conditional stability constants. After 15 days, release of Gd3+ from the nonionic linear GBCAs was about 10 times higher than from the ionic linear GBCAs. Elevated serum phosphate levels accelerated the release of Gd3+ from nonionic linear GBCAs and, to a lesser degree, from the ionic linear GBCAs. All 3 macrocyclic GBCAs remained stable in human serum at both normal and elevated phosphate levels.

Imaging-therapy computed tomography with quasi-monochromatic X-rays.

INTRODUCTION: Computed tomography (CT) is a widespread and highly precise technique working in the energy range around 50-100 keV. For radiotherapy, however, the MeV energy range enables a better dose distribution. This gap between diagnosis and therapy can be overcome by the use of a modified CT machine in combination with heavy elements targeted to the tumour and used as photoelectric radiation enhancer. MATERIALS AND METHODS: The experimental setup consists of an X-ray optical module mounted at the exit of the X-ray tube of a clinical CT. The module converts the standard fan-shaped beam into a high intensity, monochromatized and focused beam. The radiation was characterized using an energy-dispersive detection system calibrated by synchrotron radiation and gel dosimetry. The photoelectric radiation enhancement for different elements was calculated and experimentally verified. RESULTS: The X-ray optical module filters selectively the energy of the tungsten K alpha-emission line (59.3 keV) with a full width at half maximum (FWHM) of 5 keV and focused the radiation onto a focal spot which coincides with the isocentre of the gantry. This results in a steep dose gradient at the centre of rotation qualified for locoregional radiation therapy. The photon energy of the quasi-monochromatic radiation agrees with the energy range of maximal photoelectric dose enhancement for gadolinium and iodine. CONCLUSION: An additional X-ray optical module optimized for targeted therapy and photoelectric dose enhancement allows the combination of diagnosis and radiotherapy on a clinical CT.

Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions.

Recent reports suggest that nephrogenic systemic fibrosis (NSF) is associated with the administration of gadolinium (Gd)-based contrast agents (GBCAs) and in particular with the stability of the Gd-complex. The aim of this investigation was to compare GBCAs and their potential to trigger NSF. Forty-two healthy male rats received repeated intravenous injections of six different GBCAs at high doses to simulate the exposure seen in patients with severe renal dysfunction. Histopathological and immunohistochemical analysis of the skin was performed, and the concentrations of Gd, zinc and copper were measured in several tissues by inductive coupled plasma atomic emission spectroscopy. Macroscopic and histological skin changes similar to those seen in NSF patients were only observed in rats receiving Omniscan. In addition, very high concentrations of Gd were observed in the animals treated with Omniscan, and, to a lesser extent, in animals treated with OptiMARK. Significantly lower levels of Gd were found after the treatment with ionic linear agents and even less after the treatment with macrocyclic agents. The data in this investigation strongly suggest that the stability of the Gd-complex is a key factor for the development of NSF-like symptoms in this experimental setting.

Gadolinium-based contrast agents and their potential role in the pathogenesis of nephrogenic systemic fibrosis: the role of excess ligand.

PURPOSE: To investigate the role of excess ligand present in gadolinium (Gd) -based contrast agents in the development of nephrogenic systemic fibrosis (NSF). Using a dosing regimen to simulate the exposure seen in patients with severe renal impairment, we investigated the effect of excess ligand on Gd-deposition and the depletion of endogenous ions. MATERIALS AND METHODS: Gadodiamide and gadoversetamide were formulated with 0%, 5%, and 10% excess ligand. Forty-two, healthy, male Hannover Wistar rats received daily intravenous injections of each formulation over a period of 20 days. At the end of the study, histopathological analysis of the skin was performed and the concentrations of Gd, Zn, and Cu were measured in several tissues. The levels of Zn in the urine were also measured. RESULTS: The most severe skin lesions were observed after injection of formulations containing 0% free ligand and in those animals with the highest Gd concentrations in the skin. There were no significant reductions in the levels of Zn or Cu observed in the skin; however, the levels of Zn in the urine were elevated following administration of formulations with the highest amount of excess ligand. CONCLUSION: Our findings suggest that there is an inverse correlation between the amount of excess ligand present in Gd-containing contrast agents and the amount of Gd in the tissue, and further underline the importance of the inherent stability of these agents in the development of NSF.

A preclinical study to investigate the development of nephrogenic systemic fibrosis: a possible role for gadolinium-based contrast media.

OBJECTIVES: Several recent publications have suggested an association between the administration of gadolinium (Gd)-based contrast agents and the occurrence of Nephrogenic Systemic Fibrosis (NSF), an acquired disorder marked by skin thickening and fibrosis occurring in patients with severe renal dysfunction. The aim of this study was to establish a preclinical experimental setting to investigate the possible link between NSF and Gd-based contrast agents, and specifically the role of Gd and/or depletion of endogenous metal ions as possible triggers for NSF. MATERIALS AND METHODS: Thirty-five healthy male rats received repeated intravenous injections of Magnevist (gadopentetate dimeglumine; Gd-DTPA), Omniscan (gadodiamide; Gd-DTPA-BMA), or gadodiamide without caldiamide at a dose of 2.5 mmol Gd/kg body weight over at least 20 days to simulate the exposure to Gd-containing contrast agents in patients with severe renal dysfunction. In addition, caldiamide (the excess ligand in Omniscan) and Gd-ethylenediamine tetraacetic acid (Gd-EDTA) as a positive control, and saline as a negative control were studied. Histopathologic and immunohistochemical analysis of the skin was performed. Gd and zinc concentrations were measured in skin, femur, and liver tissue by atomic emission spectrometry. RESULTS: Rats receiving Gd-EDTA, gadodiamide without caldiamide, and Omniscan developed epidermal ulceration and acanthosis, dermo-epidermal clefts, minimal-to-slight dermal fibrosis, and increased dermal infiltration of different cells, partly positive for CD34 fibrocytes. No such NSF-like macroscopic lesions were observed in the saline, caldiamide, and Magnevist groups. High Gd concentrations in the skin were found in the Gd-EDTA, gadodiamide without caldiamide, and Omniscan groups. In the Magnevist group, Gd levels in the skin were 10-times lower than in the Omniscan-treated animals but elevated compared with saline. CONCLUSIONS: A preclinical experimental setting has been established where NSF-like lesions could be observed. The link between the application of Gd-based contrast media and the induction of NSF-like lesions was established. The data indicate that the observed skin lesions are related to the release of Gd and not to the depletion of endogenous ions. The investigations further suggest potential importance of the stability of Gd-based contrast agents.

Magnetic resonance imaging of atherosclerosis by targeting extracellular matrix deposition with Gadofluorine M.

As previously reported, Gadofluorine M-enhanced magnetic resonance imaging clearly demarcates atherosclerotic plaques from the normal vessel wall. To date, the underlying mechanism has remained unknown. Gadofluorine M is a gadolinium-containing macrocyclic contrast agent containing hydrophilic and hydrophobic moieties. To elucidate the mechanism of accumulation, fluorescently labeled and radioactively labeled derivates of Gadofluorine M were used to determine affinity and specificity of Gadofluorine M binding to blood serum and plaque components in vitro and for the distribution within the plaque of WHHL rabbits in vivo. Gadofluorine M binds to serum albumin, leading to a breakdown of micelles after intravenous injection. The affinity of Gadofluorine M to serum albumin is k(D) = 2 micromol/l. Gadofluorine then penetrates the atherosclerotic plaque while bound to albumin and then accumulates within the extracellular, fibrous parts of the plaque by binding to collagens, proteoglycans and tenascin, having the same affinity to these plaque constituents as to albumin. In contrast, weak binding was determined to LDL (k(D) = 2 mmol/l) and even no binding to hyaluronic acid. The driving force of binding and accumulation is the hydrophobic moiety of the molecules interacting with hydrophobic plaque materials. Thus, Gadofluorine M accumulates within the fibrous plaque or in the fibrous cap of a plaque containing high amounts of extracellular matrix components, but not in the lipid-rich areas. In combination with high-resolution MRI, Gadofluorine M might enable the detection of thin-cap fibroatheromas, also named the vulnerable plaque.

Pulmonary MR perfusion at 3.0 Tesla using a blood pool contrast agent: Initial results in a swine model.

PURPOSE: To prospectively evaluate the technical feasibility of a highly accelerated pulmonary MR perfusion protocol at 3.0T using a blood pool contrast agent in a swine model. MATERIALS AND METHODS: Twelve pigs underwent time-resolved pulmonary MR angiography (MRA) on a 3.0T MR system under anesthesia and controlled mechanical ventilation. After intravenous injection of 0.05 mmol/kg of Gadomer-17 at 4 mL/second, a fast time-resolved MRA sequence with temporal echo-sharing (three segmented k-space) and highly accelerated parallel acquisition was used to acquire 3D data sets with an in-plane resolution of 1 x 1 mm(2) (slice thickness = 6 mm) and temporal resolution of one second. Image quality was evaluated independently by two radiologists, and quantitative analysis of perfusion parameters was performed using pre-released perfusion software. RESULTS: All studies were identified by both readers as having diagnostic image quality (range = 2-3, median = 3) and there was excellent interobserver agreement (kappa = 0.89; 95% CI = 0.83, 0.95). A quantitative analysis of perfusion indices was performed, with excellent overall goodness-of-fit (chi(2) value = 1.4, degree of freedom (DF) = 1). Successfully derived perfusion parameters included the time to peak (TTP, 5.1 +/- 0.7 second), mean transit time (MTT, 6.6 +/- 0.9 second), maximal signal intensity (MSI, 1051.2 +/- 718.9 arbitrary units [A.U.]), and maximal upslope of the curve (MUS, 375.9 +/- 263.4 A.U./second). CONCLUSION: 3.0T pulmonary MR perfusion using a blood pool contrast agent in a swine model is feasible. The higher available signal-to-noise ratio (SNR) at 3.0T and the high T1 relaxivity of Gadomer-17 effectively support highly accelerated parallel acquisition, and improve the performance of time-resolved pulmonary MRA.

MRI tumor characterization using Gd-GlyMe-DOTA-perfluorooctyl-mannose-conjugate (Gadofluorine M), a protein-avid contrast agent.

The rationale and objectives were to define the MRI tumor-characterizing potential of a new protein-avid contrast agent, Gd-GlyMe-DOTA-perfluorooctyl-mannose-conjugate (Gadofluorine M; Schering AG, Berlin, Germany) in a chemically induced tumor model of varying malignancy. Because of the tendency for this agent to form large micelles in water and to bind strongly to hydrophobic sites on proteins, it was hypothesized that patterns of dynamic tumor enhancement could be used to differentiate benign from malignant lesions, to grade the severity of malignancies and to define areas of tumor necrosis. Gadofluorine M, 0.05 mmol Gd kg(-1), was administered intravenously to 28 anesthetized rats that had developed over 10 months mammary tumors of varying degrees of malignancy as a consequence of intraperitoneal administration of N-ethyl-N-nitrosourea (ENU), 45-250 mg kg(-1). These tumors ranged histologically from benign fibroadenomas to highly undifferentiated adenocarcinomas. Dynamic enhancement data were analyzed kinetically using a two-compartment tumor model to generate estimates of fractional plasma volume (fPV), apparent fractional extracellular volume (fEV*) and an endothelial transfer coefficient (K(PS)) for this contrast agent. Tumors were examined microscopically for tumor type, degree of malignancy (Scarff-Bloom-Richardson score) and location of necrosis. Eighteen tumor-bearing rats were successfully imaged. MRI data showed an immediate strong and gradually increasing tumor enhancement. K(PS) and fEV*, but not fPV obtained from tumors correlated significantly (p < 0.05) with the SBR tumor grade, r = 0.65 and 0.56, respectively. Estimates for K(PS) and fEV* but not fPV were significantly lower in a group consisting of benign and low-grade malignant tumors compared with the group of less-differentiated high-grade tumors (1.61 +/- 0.64 vs 3.37 +/- 1.49, p < 0.01; 0.45 +/- 0.17 vs 0.78 +/- 0.24, p < 0.01; and 0.076 +/- 0.048 vs 0.121 +/- 0.088, p = 0.24, respectively). It is concluded that the protein-avid MRI contrast agent Gadofluorine M enhances tumors of varying malignancy depending on the tumor grade, higher contrast agent accumulation for more malignant lesions. The results show potential utility for differentiating benign and low-grade malignant lesions from high-grade cancers.

CT angiography with gadolinium-based contrast media.

RATIONALE AND OBJECTIVES: To evaluate the potential use of gadolinium (Gd)-based contrast media, especially that of Gadovist, a 1-molar Gd medium, in computed tomography (CT) and compare our findings with standard iodinated contrast media. MATERIAL AND METHODS: Using a live rabbit and an acrylic CT body phantom for comparative CT imaging of Gd- and I-based media. The images were acquired at 80, 100, and 120 kVp, using fixed standard beam filtration. The phantom study used serial dilutions of the Magnevist and Ultravist 300 (2.4-molar I), whereas the animal study used different volumes of Gadovist, Magnevist (0.5 molar Gd), and Ultravist administered intravenously. RESULTS: At 80 kVp for the same injection volumes of Gadovist and Ultravist, the image contrast enhancement of the aorta with Gadovist was 40% lower than that of Ultravist. In the phantom studies, however, for the same kVp settings the CT image contrast was up to fourfold higher for Gd compared with iodine when comparing the same molar concentrations of the two elements in the solutions. CONCLUSION: These results indicate a potential of Gd-based media for clinical CT angiography and provide incentive for further investigation of this subject.

Gadofluorine-enhanced magnetic resonance imaging of carotid atherosclerosis in Yucatan miniswine.

OBJECTIVE: The aim of this study was to determine whether gadofluorine, a paramagnetic magnetic resonance imaging (MRI) contrast agent, selectively enhances carotid atherosclerotic plaques in Yucatan miniswine. METHODS: Atherosclerotic plaques were induced in the left carotid arteries (LCA) of Yucatan miniswine (n=3) by balloon denudation and high cholesterol diet. T1-weighted MRI was performed before and 24 hours after gadofluorine injection (at a dose of 100 micromol/kg) to assess the enhancement of the balloon-injured LCA wall relative to healthy, uninjured right carotid artery (RCA) wall. Histopathology was performed to verify the presence and composition of the atherosclerotic plaques imaged with MRI. RESULTS: Gadofluorine was found to enhance LCA atherosclerotic lesions relative to RCA wall by 21% (P<0.025) 24 hours after contrast injection. Enhancement of healthy LCA wall relative to healthy RCA wall was not observed. CONCLUSION: Gadofluorine selectively enhances carotid atherosclerotic plaques in Yucatan miniswine. Gadofluorine appears to be a promising MR contrast agent for detection of atherosclerotic plaques in vivo.

Comparison of magnetic properties of MRI contrast media solutions at different magnetic field strengths.

RATIONALE AND OBJECTIVES: To characterize and compare commercially available contrast media (CM) for magnetic resonance imaging (MRI) in terms of their relaxivity at magnetic field strengths ranging from 0.47 T to 4.7 T at physiological temperatures in water and in plasma. Relaxivities also were quantified in whole blood at 1.5 T. METHODS: Relaxivities of MRI-CM were determined by nuclear magnetic resonance (NMR) spectroscopy at 0.47 T and MRI phantom measurements at 1.5 T, 3 T, and 4.7 T, respectively. Both longitudinal (T1) and transverse relaxation times (T2) were measured by appropriate spin-echo sequences. Nuclear magnetic resonance dispersion (NMRD) profiles were also determined for all agents in water and in plasma. RESULTS: Significant dependencies of relaxivities on the field strength and solvents were quantified. Protein binding leads to both increased field strength and solvent dependencies and hence to significantly altered T1 relaxivity values at higher magnetic field strengths. CONCLUSIONS: Awareness of the field strength and solvent associated with relaxivity data is crucial for the comparison and evaluation of relaxivity values. Data observed at 0.47 T can thus be misleading and should be replaced by relaxivities measured at 1.5 T and at 3 T in plasma at physiological temperature.

VX2 carcinoma in rabbits after radiofrequency ablation: comparison of MR contrast agents for help in differentiating benign periablational enhancement from residual tumor.

PURPOSE: To prospectively compare the accuracy of a blood pool agent, SH L 643A, with that of gadopentetate dimeglumine in differentiating benign periablational enhancement from residual tumor in VX2 carcinomas in rabbits after radiofrequency (RF) ablation. MATERIALS AND METHODS: Experiment was approved by the animal care committee. Sequential MR images were obtained before and with SH L 643A (17 000 Da, 0.05 mmol/kg) and, after a 24-hour interval, gadopentetate dimeglumine (546 Da, 0.1 mmol/kg) in 12 rabbits with VX2 carcinoma in the back muscle prior to (n = 12) and early (n = 12), 1 week (n = 8), and 4 weeks (n = 4) after RF ablation. RF ablation was performed with output of 90 W but at less than 300 seconds to ensure incomplete tumor ablation. The pathologic specimens were sectioned in the same plane as MR imaging, and the enhancement ratios (ie, the ratios of postcontrast to precontrast signal intensity) and the microvessel densities of residual tumor and benign periablational enhancement were assessed. RESULTS: With SH L 643A, the peak enhancement ratios of residual tumor (1.64 +/- 0.31 [standard deviation]) were significantly higher than those of benign periablational enhancement (0.97 +/- 0.16) (P < .001). With gadopentetate dimeglumine, the peak enhancement ratios of residual tumor (1.82 +/- 0.33) were not different from those of benign periablational enhancement (1.71 +/- 0.36). In benign periablational enhancement, enhancement ratios with injection of SH L 643A were lower than those with injection of gadopentetate dimeglumine for all time points up to 30 minutes (P < .05). The microvessel density was 25.72 +/- 5.43 vessels per field of view for residual tumor and 10.37 +/- 2.88 vessels per field of view for benign periablational enhancement (P < .001). CONCLUSION: Blood pool contrast agent SH L 643A permits more accurate differentiation of benign periablational enhancement from residual tumor compared with the extracellular agent gadopentetate dimeglumine.

Lipid-rich atherosclerotic plaques detected by gadofluorine-enhanced in vivo magnetic resonance imaging.

BACKGROUND: MRI of specific components in atherosclerotic plaque may provide information on plaque stability and its potential to rupture. We evaluated gadofluorine in atherosclerotic rabbits using a new MR sequence that allows plaque detection within 1 hour after injection and assessed enhancement in lipid-rich and non-lipid-rich plaques. METHODS AND RESULTS: Twelve rabbits with aortic plaque and 6 controls underwent MRI before and up to 24 hours after gadofluorine injection (50 micromol/kg). Two T1-weighted, segmented gradient-echo sequences (TFL) were compared to enhance vessel wall delineation after injection: (1) an inversion-recovery prepulse (IR-TFL) or (2) a combination of inversion-recovery and diffusion-based flow suppression prepulses (IR-DIFF-TFL). With the use of IR-TFL at 1 hour after injection, the vessel wall was not delineated because of poor flow suppression; at 24 hours after injection, the enhancement was 37% (P<0.01). IR-DIFF-TFL showed significant enhancement after versus before contrast (1 hour: 164% [P<0.005]; 24 hours: 207% [P<0.001]). At 1 hour and 24 hours after injection, the contrast-to-noise ratio was higher with the use of IR-DIFF-TFL than with IR-TFL (1 hour: 13.0+/-7.7 versus -19.8+/-10.3 [P<0.001]; 24 hours: 15.2+/-5.9 versus 11.4+/-8.9, respectively [P=0.052]). There was no enhancement in the vessel wall after gadofluorine injection in the control group. A strong correlation was found (r2=0.87; P<0.001) between the lipid-rich areas in histological sections and signal intensity in corresponding MR images. This suggests a high affinity of gadofluorine for lipid-rich plaques. CONCLUSIONS: Gadofluorine-enhanced MRI improves atherosclerotic plaque detection. The IR-DIFF-TFL method allows early detection of atherosclerotic plaque within 1 hour after gadofluorine injection.

Early MR lymphography with gadofluorine M in rabbits.

PURPOSE: To investigate the dose and time dependency of gadofluorine M for lymph node imaging and the detection of lymph node metastases in an animal model and to compare gadofluorine M with Gadomer (both, Schering, Berlin, Germany) for lymph node enhancement. MATERIALS AND METHODS: Enhancement of popliteal and iliac lymph nodes was studied in VX2 tumor-bearing rabbits before injection and at 5-120 minutes and 24 hours after intravenous bolus injection of 0.025, 0.05, and 0.1 mmol gadolinium per kilogram of body weight gadofluorine M (six rabbits) or 0.5 mmol/kg Gadomer (eight rabbits). Effects of treatment and time point at enhancement were evaluated with repeated measures analysis of variance. Means were separated with all-pairs comparison with Tukey-Kramer adjustment. After 1.5-T magnetic resonance (MR) imaging, lymph nodes were removed, and prepared sections were stained with hematoxylin-eosin for microscopic examination. RESULTS: MR images in VX2 tumor-bearing rabbits revealed rapid and strong signal intensity increase in the functional lymph node tissue by 15 minutes after intravenous injection of gadofluorine M. Maximum enhancement of 165%-309% was observed 60-90 minutes after injection (enhancement with 0.05 and 0.1 mmol/kg significantly different from that with 0.025 mmol/kg, P < or =.05). Metastatic tissue showed only slight enhancement at early time points, resulting in high-contrast differentiation between functional and metastatic tissue. Intravenous injection of the blood-pool agent Gadomer induced only short and inhomogeneous lymph node enhancement (enhancement significantly lower [P < or =.05] than that with gadofluorine M). CONCLUSION: Findings in the study showed that gadofluorine M produces rapid lymph node accumulation. Diagnosis of lymph node metastases was shown with intravenous injection of gadofluorine M with a minimum effective diagnostic dose of 0.025 mmol/kg.

Contrast-enhanced MR imaging of postoperative scars and VX2 carcinoma in rabbits: comparison of macromolecular contrast agent and gadopentetate dimeglumine.

PURPOSE: To compare the magnetic resonance (MR) imaging enhancement patterns of a blood pool contrast agent, SH L 643A, with those of gadopentetate dimeglumine in postoperative scars and VX2 carcinomas in rabbits and to compare these enhancement patterns with microvessel density in pathologic specimens. MATERIALS AND METHODS: Eighteen rabbits with experimentally induced postoperative scars (n = 12) or VX2 carcinoma (n = 6) in the thighs underwent sequential MR imaging first with gadopentetate dimeglumine and then, 24 hours later, with SH L 643A. The enhancement ratios (ie, the ratios of postcontrast to precontrast signal intensity) and the microvessel densities of postoperative scars and VX2 carcinomas were assessed. Differences were tested for by using the Mann-Whitney U and Wilcoxon signed rank tests. RESULTS: In postoperative scars, enhancement ratios were consistently lower with injection of SH L 643A than with injection of gadopentetate dimeglumine for up to 30 minutes (P <.05). In postoperative scars, mean peak enhancement ratios were 1.29 +/- 0.15 (SD) with injection of SH L 643A and 1.61 +/- 0.31 with injection of gadopentetate dimeglumine (P <.01). In VX2 carcinomas, the enhancement ratios were not significantly different with injection of SH L 643A than with injection of gadopentetate dimeglumine at all time points. The mean difference between the enhancement ratios of the VX2 carcinomas and postoperative scars was 0.64 +/- 0.10 (range, 0.50-0.77) with SH L 643A and 0.36 +/- 0.16 (range, 0.17-0.66) with gadopentetate dimeglumine (P <.01). The mean microvessel density (in terms of vessels per field of view) was 10.7 +/- 5.5 for postoperative scars and 30.0 +/- 7.7 for VX2 carcinoma (P <.001). CONCLUSION: The difference between the enhancement ratios of postoperative scars and VX2 carcinomas with SH L 643A was greater than that with gadopentetate dimeglumine. Enhancement ratios at SH L 643A-enhanced MR imaging corresponded well with microvessel density in postoperative scars and VX2 carcinomas.

Dynamic contrast-enhanced MR imaging of VX2 carcinomas after X-irradiation in rabbits: comparison of gadopentetate dimeglumine and a macromolecular contrast agent.

RATIONALE AND OBJECTIVES: To compare enhancement patterns of gadomer-17 with those of gadopentetate dimeglumine in VX2 carcinomas after irradiation on rabbits. METHODS: Twelve rabbits with VX2 carcinoma in the thigh underwent dynamic contrast-enhanced magnetic resonance (MR) imaging with gadopentetate dimeglumine and gadomer-17 at 24-hour intervals before (n = 12), 3 days (group 1, n = 12), 1 month (group 2, n = 8) and 2 months (group 3, n = 4) after 30 Gy irradiation. After taking postirradiation MR images, 4 rabbits were killed for histopathologic examination at each time interval. The enhancement characteristics in MR imaging and morphology of tumor vessels in histopathologic specimen were assessed. RESULTS: After gadopentetate dimeglumine injection, the enhancement characteristics were not different among tumors before and after irradiation (P > 0.05). For gadomer-17, the enhancement ratios decreased after irradiation. The shape of the curves for tumor enhancement before irradiation was significantly different from curves of group 1(P < 0.05). The specimens from group 3 showed sclerosis and wall thickening in arterioles. CONCLUSIONS: Dynamic contrast-enhanced MR imaging with a gadomer-17 reveals increased capillary permeability at an early phase after irradiation and chronic obliterating vasculopathy at delayed phase.

New contrast media designed for x-ray energy subtraction imaging in digital mammography.

RATIONALE AND OBJECTIVES: In contrast-enhanced dual-energy subtraction imaging 2 images acquired postcontrast media administration at different energies are subtracted to highlight structures hidden in the absence of contrast media. X-ray spectra of the newly developed digital full-field mammography units (GE Senographe 2000 D) are dominated by the emission lines of the Mo or Rh anodes. The K-edge of Zirconium (Zr) is flanked by these 2 emission lines. Thus, the attenuation of Zr should experience a pronounced change of attenuation in parallel with a change of anodes. Under clinically relevant conditions, the contrasting behavior of Zr should be compared with that of other elements having K-edge energies outside the window spanned by the 2 anode emission lines. METHODS: Solutions containing the contrasting elements Br, Y, Zr, I, and Gd were investigated for dual-energy subtraction in digital mammography with the 2 anode/filter settings (Mo/Mo and Rh/Rh). These solutions were investigated in phantom studies in the energy range conventionally used in mammography. Additionally, the contrasting behavior of Zr and I was compared in an in vivo study in rats. RESULTS: The sweeping over the K-edge by alternating between the Mo and Rh anodes increases the detection of Zr in energy subtraction imaging at constant high voltage. This procedure does not lead to sufficient contrast enhancement for iodine-based contrast media which become detectable by increasing the high voltage to 40-49 kV. CONCLUSION: The instrumental and physical data outlined predestine Zr as contrasting element with a high potential for energy subtraction imaging in digital mammography in the energy range conventionally applied.

Detection of atherosclerotic plaque with Gadofluorine-enhanced magnetic resonance imaging.

BACKGROUND: The purpose of this study was to visualize atherosclerotic plaques independently of luminal narrowing using T1-weighted contrast-enhanced MRI. METHODS AND RESULTS: Eight Watanabe heritable hyperlipidemic (WHHL) rabbits, aged 9 to 18 months, and 8 age-matched controls (New Zealand White rabbits) underwent MRI of the aortic arch before and up to 48 hours after injection of 100 micromol/kg Gadofluorine (Schering AG). Additionally, 8 WHHL rabbits were examined with Magnevist (Schering AG). A half-Fourier acquisition single-shot turbo-spin-echo (HASTE) sequence and a T1-weighted inversion-recovery turbo fast, low-angle shot sequence were used for data acquisition. Immediately after the MR examination, the animals were killed, the aorta was stained with Sudan red, and ex vivo imaging of the stained aortic specimens was performed. Additionally, gadolinium concentrations in plaque (Sudan-positive) and normal (Sudan-negative) aortic wall segments were measured. Plain MR imaging revealed no plaques in the aortic arch in either animal group. Enhancement occurred in the aortic wall of all WHHL rabbits examined with Gadofluorine but not in the vessel wall of animals examined with Magnevist and the control group. Sudan red staining demonstrated multiple plaques in the aortic arch of all WHHL rabbits. Ex vivo imaging demonstrated that the area of hyperenhancement matched the area of plaques stained with Sudan red. The gadolinium concentration was 7+/-5 nmol/g for normal aortic wall of the control group and 368+/-30 nmol/g for aortic wall with plaque in WHHL. CONCLUSIONS: Gadofluorine enhances the imaging of atherosclerotic plaques and enables improved plaque detection of even nonstenotic lesions that are not visible on unenhanced MRI.