Characterization of hepatic fatty acids using magnetic resonance spectroscopy for the assessment of treatment response to metformin in an eNOS-/- mouse model of metabolic nonalcoholic fatty liver disease/nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide. Liver biopsy remains the gold standard for diagnosis and staging of disease. There is a clinical need for noninvasive diagnostic tools for risk stratification, follow-up, and monitoring treatment response that are currently lacking, as well as preclinical models that recapitulate the etiology of the human condition. We have characterized the progression of NAFLD in eNOS-/- mice fed a high fat diet (HFD) using noninvasive Dixon-based magnetic resonance imaging and single voxel STEAM spectroscopy-based protocols to measure liver fat fraction at 3 T. After 8 weeks of diet intervention, eNOS-/- mice exhibited significant accumulation of intra-abdominal and liver fat compared with control mice. Liver fat fraction measured by 1 H-MRS in vivo showed a good correlation with the NAFLD activity score measured by histology. Treatment of HFD-fed NOS3-/- mice with metformin showed significantly reduced liver fat fraction and altered hepatic lipidomic profile compared with untreated mice. Our results show the potential of in vivo liver MRI and 1 H-MRS to noninvasively diagnose and stage the progression of NAFLD and to monitor treatment response in an eNOS-/- murine model that represents the classic NAFLD phenotype associated with metabolic syndrome.

Enhanced Peripheral Chemoreflex Drive Is Associated with Cardiorespiratory Disorders in Mice with Coronary Heart Disease.

Coronary heart disease (CHD) is a prevalent cardiovascular disease characterized by coronary artery blood flow reductions caused by lipid deposition and oxidation within the coronary arteries. Dyslipidemia is associated with local tissue damage by oxidative stress/inflammation and carotid bodies (CB) peripheral chemoreceptors are heavily modulated by both reactive oxygen species and pro-inflammatory molecules (i.e., cytokines). Despite this, it is not know whether CB-mediated chemoreflex drive may be affected in CHD. In the present study, we evaluated peripheral CB-mediated chemoreflex drive, cardiac autonomic function, and the incidence of breathing disorders in a murine model of CHD. Compared to age-matched control mice, CHD mice showed enhanced CB-chemoreflex drive (twofold increase in the hypoxic ventilatory response), cardiac sympathoexcitation, and irregular breathing disorders. Remarkably, all these were closely linked to the enhanced CB-mediated chemoreflex drive. Our results showed that mice with CHD displayed an enhanced CB chemoreflex, sympathoexcitation, and disordered breathing and suggest that CBs may be involved in chronic cardiorespiratory alterations in the setting of CHD.

The IL-1 Family and Its Role in Atherosclerosis.

The IL-1 superfamily of cytokines is a central regulator of immunity and inflammation. The family is composed of 11 cytokines (with agonist, antagonist, and anti-inflammatory properties) and 10 receptors, all tightly regulated through decoy receptor, receptor antagonists, and signaling inhibitors. Inflammation not only is an important physiological response against infection and injury but also plays a central role in atherosclerosis development. Several clinical association studies along with experimental studies have implicated the IL-1 superfamily of cytokines and its receptors in the pathogenesis of cardiovascular disease. Here, we summarize the key features of the IL-1 family, its role in immunity and disease, and how it helps shape the development of atherosclerosis.

Multimodal assessment of acute cardiac toxicity induced by thoracic radiotherapy in cancer patients. Study protocol.

BACKGROUND: Today, cancer ranks as one of the leading causes of death. Despite the large number of novel available therapies, radiotherapy (RT) remains as the most effective non-surgical method to cure cancer patients. In fact, approximately 50% of all cancer patients receive some type of RT and among these 60% receive RT-treatment with a curative intent. However, as occurs with any other oncological therapy, RT treated patients may experience toxicity side effects that range from moderate to severe. Among these, cardiotoxicity represents a significant threat for premature death. Current methods evaluate cardiotoxic damage based on volumetric changes in the Left Ventricle Ejected Fraction (LVEF). Indeed, a 10% drop in LVEF is commonly used as indicator of cardiotoxicity. More recently, a number of novel techniques have been developed that significantly improve specificity and sensitivity of heart's volumetric changes and early detection of cardiotoxicity even in asymptomatic patients. Among these, the Strain by Speckle Tracking (SST) is a technique based on echocardiographic analysis that accurately evaluates myocardial deformation during the cardiac cycle (ventricular and atrial function). Studies also suggest that Magnetic Resonance Imaging (MRI) is a high-resolution technique that enables a better visualization of acute cardiac damage. METHODOLOGY: This protocol will evaluate changes in SST and MRI in cancer patients that received thoracic RT. Concomitantly, we will assess changes in serum biomarkers of cardiac damage in these patients, including: high-sensitivity cardiac Troponin-T (hscTnT), N-Terminal pro-Brain Natriuretic Peptide (NTproBNP) and Circulating Endothelial Cells (CECs), a marker of endothelial dysfunction and vascular damage. DISCUSSION: The presented protocol is to our knowledge the first to prospectively and with a multimodal approach, study serological and image biomarkers off early cardiac damage due to radiotherapy. With a practical clinical approach we will seek early changes that could potentially be in the future be linked to clinical mayor events with consequences for cancer survivors.

Sustained Focal Vascular Inflammation Accelerates Atherosclerosis in Remote Arteries.

OBJECTIVE: Evidence from preclinical and clinical studies has demonstrated that myocardial infarction promotes atherosclerosis progression. The impact of focal vascular inflammation on the progression and phenotype of remote atherosclerosis remains unknown. Approach and Results: We used a novel ApoE-/- knockout mouse model of sustained arterial inflammation, initiated by mechanical injury in the abdominal aorta. Using serial in vivo molecular MRI and ex vivo histology and flow cytometry, we demonstrate that focal arterial inflammation triggered by aortic injury, accelerates atherosclerosis in the remote brachiocephalic artery. The brachiocephalic artery atheroma had distinct histological features including increased plaque size, plaque permeability, necrotic core to collagen ratio, infiltration of more inflammatory monocyte subsets, and reduced collagen content. We also found that arterial inflammation following focal vascular injury evoked a prolonged systemic inflammatory response manifested as a persistent increase in serum IL-6 (interleukin 6). Finally, we demonstrate that 2 therapeutic interventions-pravastatin and minocycline-had distinct anti-inflammatory effects at the plaque and systemic level. CONCLUSIONS: We show for the first time that focal arterial inflammation in response to vascular injury enhances systemic vascular inflammation, accelerates remote atheroma progression and induces plaques more inflamed, lipid-rich, and collagen-poor in the absence of ischemic myocardial injury. This inflammatory cascade is modulated by pravastatin and minocycline treatments, which have anti-inflammatory effects at both plaque and systemic levels that mitigate atheroma progression.

Assessment of hepatic fatty acids during non-alcoholic steatohepatitis progression using magnetic resonance spectroscopy.

INTRODUCTION AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver abnormalities including steatosis, steatohepatitis, fibrosis, and cirrhosis. Liver biopsy remains the gold standard method to determine the disease stage in NAFLD but is an invasive and risky procedure. Studies have previously reported that changes in intrahepatic fatty acids (FA) composition are related to the progression of NAFLD, mainly in its early stages. The aim of this study was to characterize the liver FA composition in mice fed a Choline-deficient L-amino-defined (CDAA) diet at different stages of NAFLD using magnetic resonance spectroscopy (MRS). METHODS: We used in-vivo MRS to perform a longitudinal characterization of hepatic FA changes in NAFLD mice for 10 weeks. We validated our findings with ex-vivo MRS, gas chromatography-mass spectrometry and histology. RESULTS: In-vivo and ex-vivo results showed that livers from CDAA-fed mice exhibit a significant increase in liver FA content as well as a change in FA composition compared with control mice. After 4 weeks of CDAA diet, a decrease in polyunsaturated and an increase in monounsaturated FA were observed. These changes were associated with the appearance of early stages of steatohepatitis, confirmed by histology (NAFLD Activity Score (NAS) = 4.5). After 10 weeks of CDAA-diet, the liver FA composition remained stable while the NAS increased further to 6 showing a combination of early and late stages of steatohepatitis. CONCLUSION: Our results suggest that monitoring lipid composition in addition to total water/fat with MRS may yield additional insights that can be translated for non-invasive stratification of high-risk NAFLD patients.

Metabolite cycled liver 1 H MRS on a 7 T parallel transmit system.

INTRODUCTION: Single-voxel 1 H MRS in body applications often suffers from respiratory and other motion induced phase and frequency shifts, which lead to incoherent averaging and hence to suboptimal results. METHODS: Here we show the application of metabolite cycling (MC) for liver STEAM-localized 1 H MRS on a 7 T parallel transmit system, using eight transmit-receive fractionated dipole antennas with 16 additional, integrated receive loops. MC-STEAM measurements were made in six healthy, lean subjects and compared with STEAM measurements using VAPOR water suppression. Measurements were performed during free breathing and during synchronized breathing, for which the subjects did breathe in between the MRS acquisitions. Both intra-session repeatability and inter-session reproducibility of liver lipid quantification with MC-STEAM and VAPOR-STEAM were determined. RESULTS: The preserved water signal in MC-STEAM allowed for robust phase and frequency correction of individual acquisitions before averaging, which resulted in in vivo liver spectra that were of equal quality when measurements were made with free breathing or synchronized breathing. Intra-session repeatability and inter-session reproducibility of liver lipid quantification were better for MC-STEAM than for VAPOR-STEAM. This may also be explained by the more robust phase and frequency correction of the individual MC-STEAM acquisitions as compared with the VAPOR-STEAM acquisitions, for which the low-signal-to-noise ratio lipid signals had to be used for the corrections. CONCLUSION: Non-water-suppressed MC-STEAM on a 7 T system with parallel transmit is a promising approach for 1 H MRS applications in the body that are affected by motion, such as in the liver, and yields better repeatability and reproducibility compared with water-suppressed measurements.

Honeybee Pollen Extracts Reduce Oxidative Stress and Steatosis in Hepatic Cells.

Nonalcoholic fatty liver disease (NAFLD) is a major cause of morbidity and mortality worldwide. Additional therapies using functional foods and dietary supplements have been investigated and used in clinical practice, showing them to be beneficial. Honeybee pollen from Chile has shown a large concentration of phenolic compounds and high antioxidant activity. In this work, we characterized twenty-eight bee pollen extracts from the central zone of Chile according to botanical origin, phenolic profile, quercetin concentration, and antioxidant activity (FRAP and ORAC-FL). Our results show a statistically significant positive correlation between total phenolic content and antioxidant capacity. Selected samples were evaluated on the ability to reverse the steatosis in an in vitro cell model using Hepa1-6 cells. The pollen extracts protected Hepa1-6 cells against oxidative damage triggered by 2,2'-azo-bis(2-amidinopropane) dihydrochloride (AAPH)derived free radicals. This effect can be credited to the ability of the phenolic compounds present in the extract to protect the liver cells from chemical-induced injury, which might be correlated to their free radical scavenging potential. Additionally, bee pollen extracts reduce lipid accumulation in a cellular model of steatosis. In summary, our results support the antioxidant, hepatoprotective, and anti-steatosis effect of bee pollen in an in vitro model.

Sarcopenia in a mice model of chronic liver disease: role of the ubiquitin-proteasome system and oxidative stress.

Sarcopenia is the loss of muscle mass and strength produced by aging or secondary to chronic diseases such as chronic liver disease (CLD). Although not all types of sarcopenia involve the same features, the most common are decreased fiber diameter and myosin heavy chain (MHC) levels, increased activity of ubiquitin-proteasome system (UPS) and reactive oxygen species (ROS). In this study, we aim to characterize the development of sarcopenia secondary to CLD induced by the hepatotoxin 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). For this purpose, four-months-old male C57BL6 mice were fed with normal diet or DDC supplemented diet for 6 weeks. Functional tests to evaluate muscle strength, mobility, and motor skills were performed in alive mice. The muscle strength in isolated gastrocnemius was also assayed via electrophysiological measurements. Morphometric measures of fibers' diameter, total and ubiquitinated protein levels of myosin heavy chain (MHC), E3 ubiquitin ligases, ROS, and oxidation-dependent modified proteins in gastrocnemius tissue were also determined. Our results demonstrated that mice fed the DDC diet developed muscle wasting as evidenced by a loss of muscle mass and decreased muscle strength. The muscles of mice fed with DDC diet have a decreased diameter of fibers and MHC levels, also as increased MuRF-1 and atrogin-1 protein levels, ROS levels, and oxidation-modified protein levels. Additionally, control and DDC mice have the same food and water intake as well as mobility. Our results demonstrate mice with CLD develop sarcopenia involving decreased levels of myofibrillar proteins, increased UPS, and oxidative stress, but not for impaired caloric intake or immobility.

Variability of 4D flow parameters when subjected to changes in MRI acquisition parameters using a realistic thoracic aortic phantom.

PURPOSE: To assess the variability of peak flow, mean velocity, stroke volume, and wall shear stress measurements derived from 3D cine phase contrast (4D flow) sequences under different conditions of spatial and temporal resolutions. METHODS: We performed controlled experiments using a thoracic aortic phantom. The phantom was connected to a pulsatile flow pump, which simulated nine physiological conditions. For each condition, 4D flow data were acquired with different spatial and temporal resolutions. The 2D cine phase contrast and 4D flow data with the highest available spatio-temporal resolution were considered as a reference for comparison purposes. RESULTS: When comparing 4D flow acquisitions (spatial and temporal resolution of 2.0 × 2.0 × 2.0 mm3 and 40 ms, respectively) with 2D phase-contrast flow acquisitions, the underestimation of peak flow, mean velocity, and stroke volume were 10.5, 10 and 5%, respectively. However, the calculated wall shear stress showed an underestimation larger than 70% for the former acquisition, with respect to 4D flow, with spatial and temporal resolution of 1.0 × 1.0 × 1.0 mm3 and 20 ms, respectively. CONCLUSIONS: Peak flow, mean velocity, and stroke volume from 4D flow data are more sensitive to changes of temporal than spatial resolution, as opposed to wall shear stress, which is more sensitive to changes in spatial resolution. Magn Reson Med 79:1882-1892, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Three-dimensional quantification of vorticity and helicity from 3D cine PC-MRI using finite-element interpolations.

PURPOSE: We propose a 3D finite-element method for the quantification of vorticity and helicity density from 3D cine phase-contrast (PC) MRI. METHODS: By using a 3D finite-element method, we seamlessly estimate velocity gradients in 3D. The robustness and convergence were analyzed using a combined Poiseuille and Lamb-Ossen equation. A computational fluid dynamics simulation was used to compared our method with others available in the literature. Additionally, we computed 3D maps for different 3D cine PC-MRI data sets: phantom without and with coarctation (18 healthy volunteers and 3 patients). RESULTS: We found a good agreement between our method and both the analytical solution of the combined Poiseuille and Lamb-Ossen. The computational fluid dynamics results showed that our method outperforms current approaches to estimate vorticity and helicity values. In the in silico model, we observed that for a tetrahedral element of 2 mm of characteristic length, we underestimated the vorticity in less than 5% with respect to the analytical solution. In patients, we found higher values of helicity density in comparison to healthy volunteers, associated with vortices in the lumen of the vessels. CONCLUSIONS: We proposed a novel method that provides entire 3D vorticity and helicity density maps, avoiding the used of reformatted 2D planes from 3D cine PC-MRI. Magn Reson Med 79:541-553, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Lumbar paraspinal muscle fat infiltration is independently associated with sex, age, and inter-vertebral disc degeneration in symptomatic patients.

PURPOSE: To determine the association of paraspinal muscles and psoas relative cross-sectional area (RCSA) and fat signal fraction (FSF) with sex, age, and intervertebral disc degeneration (IDD) in symptomatic patients. METHODS: We retrospectively evaluated 80 adult patients with spinal symptoms using T2-weighted magnetic resonance images. We determined RCSA and FSF of the paraspinal muscles (erector spinae and multifidus) and psoas from L1-L2 to L5-S1; we determined IDD using the Pfirrmann classification. We compared differences in muscle RCSA and FSF based on sex and IDD, and we correlated age and IDD with RCSA and FSF. Using multivariate linear regression analyses, we determined the impact of sex, age, and IDD on RCSA and FSF. RESULTS: Men exhibited larger psoas RCSA but not larger paraspinal muscles RCSA than women. Women had larger FSF in the paraspinal muscles and psoas. Increasing IDD was associated with larger FSF if ≥2 Pfirrmann grades were observed. IDD correlated with FSF of the paraspinal muscles, and age correlated with FSF of the paraspinal muscles and psoas. IDD was less consistently correlated with RCSA, but age correlated negatively with RCSA of all three muscles. Linear regression analyses demonstrated that sex, age, and IDD were each independently associated with FSF of the paraspinal muscles; additionally, sex and age, but not IDD, were associated with psoas FSF. RCSA was less consistently influenced by these three variables. CONCLUSIONS: Sex, age, and IDD are independently associated with paraspinal muscles FSF; only sex and age influence psoas FSF.

Is a single-level measurement of paraspinal muscle fat infiltration and cross-sectional area representative of the entire lumbar spine?

PURPOSE: Lumbar paraspinal muscle morphology has recently been evaluated in several studies with conflicting results. Several studies have performed single-slice evaluations of paraspinal muscle morphology, whereas other studies have done a multi-level assessment; this methodological difference might explain the observed different results. Our study evaluated if a single-slice axial measurement is representative of the entire lumbar musculature. METHODS: We included 80 adult patients who were consecutively evaluated with magnetic resonance imaging (MRI) for spinal symptoms. Using T2-weighted axial images, we measured the fat signal fractions (FSF) and cross-sectional area (CSA) of the erector spinae and multifidus at the five levels of the lumbar spine (from L1-L2 to L5-S1). We used the ANOVA test for repeated measurements (with Bonferroni correction) to compare the FSF and CSA among the levels. RESULTS: Erector spinae showed an increasing FSF from L1-L2 to L5-S1; all erector spinae FSF comparisons among the different levels were significantly different. Multifidus FSF also increased caudally below L2-L3, although significant differences were observed only with two or more levels of distance. The CSA of the erector spinae showed a caudal decrease (L4-L5 and L5-S1 being significantly smaller than all the levels above). The CSA of the multifidus showed that all levels exhibited a significantly different area compared to their adjacent level (except L5-S1 compared to L4-L5). CONCLUSIONS: No single-level FSF or CSA is representative of the whole lumbar spine. A standardized multi-level evaluation of the paraspinal musculature should be used in future research.

[Contrast-enhanced spectral mammography. Experience in 465 examinations]. / Rendimiento de la mamografía espectral de energía dual con contraste en la detección de cáncer de mama: experiencia en un centro de referencia.

BACKGROUND: Contrast-enhanced spectral mammography or "contrast mammography" has a better cost effectiveness than breast magnetic resonance for confirmation of suspicious lesions detected on breast screening programs. AIM: To report the experience of a single center in Santiago. MATERIAL AND METHODS: All patients referred for contrast mammography between July 2015 and October 2017 were studied. We recorded the patient risk factors for breast cancer. In 85 patients with suspicious lesions, biopsy results were available. RESULTS: We analyzed 465 contrast mammographies. The most common clinical indications were suspicion of cancer and previous inconclusive studies. Mass type lesions were detected in 33% of the studies. Non-mass-type lesions were observed in 10% of cases and findings compatible with papillomatosis in 2%. Fifty five percent of the studies had no visible lesions. In the 85 patients with a pathological study of the biopsy, the sensitivity of the contrast mammography was 100%, with a diagnostic accuracy of 85%, positive and negative predictive values of 82 and 100% respectively. CONCLUSIONS: Contrast mammography can be of great use for the assessment of patients with an altered conventional mammography, before indicating a magnetic resonance imaging or a percutaneous biopsy.

Total liver fat quantification using three-dimensional respiratory self-navigated MRI sequence.

PURPOSE: MRI can produce quantitative liver fat fraction (FF) maps noninvasively, which can help to improve diagnoses of fatty liver diseases. However, most sequences acquire several two-dimensional (2D) slices during one or more breath-holds, which may be difficult for patients with limited breath-holding capacity. A whole-liver 3D FF map could also be obtained in a single acquisition by applying a reliable breathing-motion correction method. Several correction techniques are available for 3D imaging, but they use external devices, interrupt acquisition, or jeopardize the spatial resolution. To overcome these issues, a proof-of-concept study introducing a self-navigated 3D three-point Dixon sequence is presented here. METHODS: A respiratory self-gating strategy acquiring a center k-space profile was integrated into a three-point Dixon sequence. We obtained 3D FF maps from a water-fat emulsions phantom and fifteen volunteers. This sequence was compared with multi-2D breath-hold and 3D free-breathing approaches. RESULTS: Our 3D three-point Dixon self-navigated sequence could correct for respiratory-motion artifacts and provided more precise FF measurements than breath-hold multi-2D and 3D free-breathing techniques. CONCLUSION: Our 3D respiratory self-gating fat quantification sequence could correct for respiratory motion artifacts and yield more-precise FF measurements. Magn Reson Med 76:1400-1409, 2016. © 2015 International Society for Magnetic Resonance in Medicine.

Realistic aortic phantom to study hemodynamics using MRI and cardiac catheterization in normal and aortic coarctation conditions.

PURPOSE: To design and characterize a magnetic resonance imaging (MRI)-compatible aortic phantom simulating normal and aortic coarctation (AoCo) conditions and to compare its hemodynamics with healthy volunteers and AoCo patients. MATERIALS AND METHODS: The phantom is composed of an MRI-compatible pump, control unit, aortic model, compliance chamber, nonreturn, and shutoff valves. The phantom without and with AoCo (13, 11, and 9 mm) was studied using 2D and 3D phase-contrast data and with a catheterization unit to measure pressures. The phantom data were compared with the mean values of 10 healthy volunteers and two AoCo patients. RESULTS: Hemodynamic parameters in the normal phantom and healthy volunteers were: heart rate: 68/61 bpm, cardiac output: 3.5/4.5 L/min, peak flow and peak velocity (Vpeak) in the ascending aorta (AAo): 270/357 mL/s (significantly, P < 0.05) and 97/107 cm/s (not significantly, P = 0.16), and pressure in the AAo of the normal phantom of 131/58 mmHg. Hemodynamic parameters in the 13, 11, and 9 mm coarctation phantoms and Patients 1 and 2 were: heart rate: 75/75/75/97/78 bpm, cardiac output: 3.3/3.0/2.9/4.0/5.8 L/min, peak flow in the AAo: 245/265/215/244/376 mL/s, Vpeak in the AAo: 96/95/81/196/187 cm/s, Vpeak after the AoCo: 123/187/282/247/165 cm/s, pressure in the AAo: 124/56, 127/51, 133/50, 120/51 and 87/39 mmHg, and a trans-coarctation systolic pressure gradient: 7, 10, 30, 20, and 11 mmHg. CONCLUSION: We propose and characterize a normal and an AoCo phantom, whose hemodynamics, including velocity, flow, and pressure data are within the range of healthy volunteers and patients with AoCo. J. Magn. Reson. Imaging 2016;44:683-697.

Fibrin-targeted magnetic resonance imaging allows in vivo quantification of thrombus fibrin content and identifies thrombi amenable for thrombolysis.

OBJECTIVE: Deep venous thrombosis is a major health problem. Thrombolytic therapies are effective in recanalizing the veins and preventing post-thrombotic complications, but there is no consensus on selection criteria. The aim of this study was to investigate a fibrin-specific MRI contrast agent (EP-2104R) for the accurate quantification of thrombus' fibrin content in vivo and for the identification of thrombus suitable for thrombolysis. APPROACH AND RESULTS: Venous thrombosis was induced in the inferior vena cava of 8- to 10-week-old male BALB/C mice and MRI performed 2, 4, 7, 10, 14, and 21 days later. Eighteen mice were scanned at each time point pre and 2 hours post injection of EP-2104R (8.0 µmol/kg) with 12 mice at each time point used to correlate fibrin contrast uptake with thrombus' histological stage and fibrin content. Six mice at each time point were immediately subjected to intravascular thrombolytic therapy (10 mg/kg of tissue-type plasminogen activator). Mice were imaged to assess response to lytic therapy 24 hours after thrombolytic treatment. Two mice at each time point were scanned post injection of 0.2 mmol/kg of Gd-DTPA (gadolinium with diethylenetriaminepentacetate, Magnevist, Schering AG, Berlin, Germany) for control purpose. Contrast uptake was correlated positively with the fibrin content of the thrombus measured by Western blotting (R(2)=0.889; P<0.001). Thrombus relaxation rate (R1) post contrast and the change in visualized thrombus size on late gadolinium enhancement inversion recovery MRI pre-EP-2104R and post-EP-2104R injection were the best predictors for successful thrombolysis (area under the curve, 0.989 [95% confidence interval, 0.97-1.00] and 0.994 [95% confidence interval, 0.98-1.00] respectively). CONCLUSIONS: MRI with a fibrin-specific contrast agent accurately estimates thrombus fibrin content in vivo and identifies thrombi that are amenable for thrombolysis.

Magnetic resonance T1 relaxation time of venous thrombus is determined by iron processing and predicts susceptibility to lysis.

BACKGROUND: The magnetic resonance longitudinal relaxation time (T1) changes with thrombus age in humans. In this study, we investigate the possible mechanisms that give rise to the T1 signal in venous thrombi and whether changes in T1 relaxation time are informative of the susceptibility to lysis. METHODS AND RESULTS: Venous thrombosis was induced in the vena cava of BALB/C mice, and temporal changes in T1 relaxation time correlated with thrombus composition. The mean T1 relaxation time of thrombus was shortest at 7 days following thrombus induction and returned to that of blood as the thrombus resolved. T1 relaxation time was related to thrombus methemoglobin formation and further processing. Studies in inducible nitric oxide synthase (iNOS(-/-))-deficient mice revealed that inducible nitric oxide synthase mediates oxidation of erythrocyte lysis-derived iron to paramagnetic Fe3+, which causes thrombus T1 relaxation time shortening. Studies using chemokine receptor-2-deficient mice (Ccr2(-/-)) revealed that the return of the T1 signal to that of blood is regulated by removal of Fe3+ by macrophages that accumulate in the thrombus during its resolution. Quantification of T1 relaxation time was a good predictor of successful thrombolysis with a cutoff point of <747 ms having a sensitivity and specificity to predict successful lysis of 83% and 94%, respectively. CONCLUSIONS: The source of the T1 signal in the thrombus results from the oxidation of iron (released from the lysis of trapped erythrocytes in the thrombus) to its paramagnetic Fe3+ form. Quantification of T1 relaxation time appears to be a good predictor of the success of thrombolysis.

Vascular remodeling and plaque vulnerability in a rabbit model of atherosclerosis: comparison of delayed-enhancement MR imaging with an elastin-specific contrast agent and unenhanced black-blood MR imaging.

PURPOSE: To compare delayed-enhancement (DE) magnetic resonance (MR) imaging with an elastin-specific contrast agent and unenhanced black-blood (BB) MR imaging with regard to vessel wall delineation and assessment of vascular remodeling and to test the prospective value for predicting plaque disruption in a rabbit model of atherosclerosis. MATERIALS AND METHODS: All procedures were approved by the animal ethics committee. Atherosclerosis was induced in 14 New Zealand White rabbits by means of a 1% cholesterol diet and endothelial denudation. Plaque disruption was triggered with Russell's viper venom and histamine. Animals with atherosclerosis were imaged before triggering to identify plaques and vascular remodeling and after triggering to identify thrombus. Plaques were classified as nondisrupted (stable) or disrupted (vulnerable). Control rabbits fed a regular diet were imaged twice. Unenhanced T1-weighted BB MR imaging, DE MR imaging with an elastin-specific contrast agent, and T1 mapping were used to assess vascular remodeling and calculate the plaque area and vessel wall relaxation rate (R1 = 1/T1). Elastin was quantified by using elastica-van Gieson stain. Group comparisons were analyzed with the Mann-Whitney or paired t test. Agreement between methods was performed with Bland-Altman analysis. RESULTS: Unenhanced T1-weighted BB MR imaging and DE MR imaging showed that, compared with nondisrupted plaques, disrupted plaques had larger plaque area (T1-weighted BB MR imaging: 5.1 mm(2) vs 5.7 mm(2); DE MR imaging: 6.0 mm(2) vs 7.9 mm(2); P < .001) and vessel area (T1-weighted BB MR imaging: 11.8 mm(2) vs 14.3 mm(2); DE MR imaging: 10.8 mm(2) vs 13.9 mm(2); P < .001) and underwent positive remodeling. Assessment of positive remodeling with DE MR imaging enabled better prediction of plaque disruption compared to that with unenhanced T1-weighted BB imaging (sensitivity: 83.7% vs 58.1%). DE MR imaging showed a stronger agreement with histologic findings, whereas the vessel area was overestimated with unenhanced T1-weighted BB imaging. CONCLUSION: Compared with unenhanced T1-weighted BB MR imaging, DE MR imaging with an elastin-specific contrast agent enables more accurate assessment of vascular remodeling in the prediction of vulnerable plaque.