Quantitative assessment of portal hypertension with bi-parametric dual-frequency hepatic MR elastography in mouse models.

OBJECTIVES: To determine the potential of bi-parametric dual-frequency hepatic MR elastography (MRE) for predicting portal pressure (PP) in mouse models of portal hypertension (PHTN) with the presence of varying hepatic fibrosis. METHODS: We studied 73 wild-type male mice, including 22 mice with hepatic congestion, 20 mice with cholestatic liver injury, and 31 age-matched sham mice. Hepatic shear stiffness (SS) and volumetric strain (VS) were calculated by 3D MRE acquired at 80 and 200 Hz. We measured PP immediately after MRE. Liver fibrosis was verified by hydroxyproline assay. We predicted PP by fitting generalized linear models with single- and dual-frequency SS and VS, respectively. The relationship between predicted and actual PP was evaluated by Spearman's correlation. We compared the prediction accuracy of portal hypertension for all models with DeLong tests at a significance level of 0.05. RESULTS: Animals with congestive or cholestatic liver disease developed significant PHTN and hepatic fibrosis to varying degrees. In both models, SS increased, while VS decreased significantly compared with shams. All bi-parametric models had high diagnostic accuracy for PHTN. The dual-frequency models (AUCs: 0.90 [81-95%], 0.91 [81-95%]) had substantially or significantly higher accuracy than single-frequency ones (AUCs: 0.83 [71-91%], and 0.78 [66-87%]). The predicted PP of dual-frequency models also showed stronger correlations with actual PP than single-frequency predictions. CONCLUSIONS: The bi-parametric dual-frequency model improved the diagnostic accuracy of liver MRE in diagnosing PHTN in preclinical models. This technical advance has the potential to monitor PHTN progression and treatment efficacy in the presence of varying fibrosis. KEY POINTS: • Bi-parametric hepatic MR elastography can predict portal pressure. • The prediction models of shear stiffness and volumetric strain with dual-frequency measurements demonstrate high diagnostic accuracy (AUCs > 0.9) in two different portal hypertension mouse models with varying fibrosis.

Assessment of advanced hepatic MR elastography methods for susceptibility artifact suppression in clinical patients.

PURPOSE: To assess the success rate, image quality, and the ability to stage liver fibrosis of a standard 2D gradient-recalled echo (GRE) and four different spin-echo (SE) magnetic resonance elastography (MRE) sequences in patients with different liver iron concentrations. MATERIALS AND METHODS: A total of 332 patients who underwent 3T MRE examinations that included liver fat and iron quantification were enrolled, including 136 patients with all five MRE techniques. Thirty-four patients had biopsy results for fibrosis staging. The liver stiffness, region of interest area, image quality, and success rate of the five sequences were compared in 115/136 patients. The area under the receiver operating characteristic curves (AUCs) and the accuracies for diagnosing early-stage fibrosis and advanced fibrosis were compared. The effect of BMI (body mass index), the R2* relaxation time, and fat fraction on the image quality and liver stiffness measurements were analyzed. RESULTS: The success rates were significantly higher in the four SE sequences (99.1-100%) compared with GRE MRE (85.3%) (all P < 0.001). There were significant differences of the mean ROI area between every pair of sequences (all P < 0.0001). There were no significant differences in the AUC of the five MRE sequences for discriminating advanced fibrosis (10 P-values ranging from 0.2410-0.9171). R2* had a significant effect on the success rate and image quality for the noniron 2D echo-planar imaging (EPI), 3D EPI and 2D GRE (all P < 0.001) sequences. BMI had a significant effect on the iron 2D EPI (P = 0.0230) and iron 2D SE (P = 0.0040) sequences. CONCLUSION: All five techniques showed good diagnostic performance in staging liver fibrosis. The SE MRE sequences had higher success rates and better image quality than GRE MRE in 3T clinical hepatic imaging. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:976-987.

Regional assessment of in vivo myocardial stiffness using 3D magnetic resonance elastography in a porcine model of myocardial infarction.

PURPOSE: The stiffness of a myocardial infarct affects the left ventricular pump function and remodeling. Magnetic resonance elastography (MRE) is a noninvasive imaging technique for measuring soft-tissue stiffness in vivo. The purpose of this study was to investigate the feasibility of assessing in vivo regional myocardial stiffness with high-frequency 3D cardiac MRE in a porcine model of myocardial infarction, and compare the results with ex vivo uniaxial tensile testing. METHODS: Myocardial infarct was induced in a porcine model by embolizing the left circumflex artery. Fourteen days postinfarction, MRE imaging was performed in diastole using an echocardiogram-gated spin-echo echo-planar-imaging sequence with 140-Hz vibrations and 3D MRE processing. The MRE stiffness and tensile modulus from uniaxial testing were compared between the remote and infarcted myocardium. RESULTS: Myocardial infarcts showed increased in vivo MRE stiffness compared with remote myocardium (4.6 ± 0.7 kPa versus 3.0 ± 0.6 kPa, P = 0.02) within the same pig. Ex vivo uniaxial mechanical testing confirmed the in vivo MRE results, showing that myocardial infarcts were stiffer than remote myocardium (650 ± 80 kPa versus 110 ± 20 kPa, P = 0.01). CONCLUSIONS: These results demonstrate the feasibility of assessing in vivo regional myocardial stiffness with high-frequency 3D cardiac MRE. Magn Reson Med 79:361-369, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Cardiac MR elastography for quantitative assessment of elevated myocardial stiffness in cardiac amyloidosis.

PURPOSE: To evaluate if cardiac magnetic resonance elastography (MRE) can measure increased stiffness in patients with cardiac amyloidosis. Myocardial tissue stiffness plays an important role in cardiac function. A noninvasive quantitative imaging technique capable of measuring myocardial stiffness could aid in disease diagnosis, therapy monitoring, and disease prognostic strategies. We recently developed a high-frequency cardiac MRE technique capable of making noninvasive stiffness measurements. MATERIALS AND METHODS: In all, 16 volunteers and 22 patients with cardiac amyloidosis were enrolled in this study after Institutional Review Board approval and obtaining formal written consent. All subjects were imaged head-first in the supine position in a 1.5T closed-bore MR imager. 3D MRE was performed using 5 mm isotropic resolution oblique short-axis slices and a vibration frequency of 140 Hz to obtain global quantitative in vivo left ventricular stiffness measurements. The median stiffness was compared between the two cohorts. An octahedral shear strain signal-to-noise ratio (OSS-SNR) threshold of 1.17 was used to exclude exams with insufficient motion amplitude. RESULTS: Five volunteers and six patients had to be excluded from the study because they fell below the 1.17 OSS-SNR threshold. The myocardial stiffness of cardiac amyloid patients (median: 11.4 kPa, min: 9.2, max: 15.7) was significantly higher (P = 0.0008) than normal controls (median: 8.2 kPa, min: 7.2, max: 11.8). CONCLUSION: This study demonstrates the feasibility of 3D high-frequency cardiac MRE as a contrast-agent-free diagnostic imaging technique for cardiac amyloidosis. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2017;46:1361-1367.

MR elastography for the assessment of hepatic fibrosis in patients with chronic hepatitis B infection: does histologic necroinflammation influence the measurement of hepatic stiffness?

PURPOSE: To determine the diagnostic performance of magnetic resonance (MR) elastography for the staging of hepatic fibrosis and to evaluate the influence of necroinflammation on hepatic stiffness in patients with chronic hepatitis B virus (HBV) infection by using histopathologic findings as the reference standard. MATERIALS AND METHODS: One hundred thirteen consecutive patients with chronic HBV infection were recruited prospectively in this institutional review board-approved study after providing written informed consent between March 2012 and October 2013. The stiffness measurements were obtained by using two-dimensional gradient-echo MR elastography with a 3.0-T MR system. The METAVIR scoring system was used for the assessment of fibrosis ("F" stage) and necroinflammation ("A" grade). The predictive ability of MR elastography was evaluated by using the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC). Multiple linear regression analyses were conducted to determine the relationship between hepatic stiffness and the variables that showed a significant association in the univariate analysis or those that were of interest for comparison with earlier work (histologic scores, sex, age, aspartate aminotransferase level, and aspartate aminotransferase/alanine aminotransferase ratio). RESULTS: MR elastography showed excellent performance for characterization of ≥ F1, ≥ F2, ≥ F3, and F4 findings, with AUC values of 0.961, 0.986, 1.000, and 0.998, respectively. It showed a moderate capability for evaluation of necroinflammatory activity of ≥ A1, ≥ A2, and A3 (AUC = 0.806, 0.834, and 0.906, respectively). Multiple linear regression analysis showed that fibrosis, necroinflammation, and sex were independently associated with hepatic stiffness (ß = 0.799, 0.277, and 0.070, respectively; P < .05). For pairwise comparisons, log-transformed hepatic stiffness showed no difference between (a) groups F0/A2-3 and F1/A0-1 and (b) groups F1/A2-3 and F2/A0-1 (P > .99 and P = .486, respectively). CONCLUSION: MR elastography demonstrated excellent performance for distinguishing the stages of hepatic fibrosis in patients with chronic HBV infection. For hepatic tissue with ≤ F2 fibrosis, necroinflammation can account for a substantial fraction of the increase in hepatic stiffness.

MR elastography derived shear stiffness--a new imaging biomarker for the assessment of early tumor response to chemotherapy.

PURPOSE: The overall goal is to develop magnetic resonance elastography derived shear stiffness as a biomarker for the early identification of chemotherapy response, allowing dose, agent type and treatment regimen to be tailored on a per patient basis, improving therapeutic outcome and minimizing normal tissue toxicity. The specific purpose of this study is to test the feasibility of this novel biomarker to measure the treatment response in a well-known chemotherapy model. METHODS: Tumors were grown in the right flank of genetically modified mice by subcutaneous injection of DoHH2 (non-Hodgkin's lymphoma) cells. Magnetic resonance elastography was used to quantify tumor stiffness before and after injection of a chemotherapeutic agent or saline. Histological tests were also performed on the tumors. RESULTS: A significant decrease (P < 0.0001) in magnetic resonance elastography-derived tumor shear stiffness was observed within 4 days of chemotherapy treatment, while no appreciable change was observed in saline-treated tumors. No significant change in volume occurred at this early stage, but there were decreased levels of cellular proliferation in chemotherapy-treated tumors. CONCLUSION: These results demonstrate that magnetic resonance elastography-derived estimates of shear stiffness reflect an initial response to cytotoxic therapy and suggest that this metric could be an early and sensitive biomarker of tumor response to chemotherapy.

Assessment of in vivo laser ablation using MR elastography with an inertial driver.

PURPOSE: To evaluate the feasibility of using MR Elastography (MRE) to monitor tissue coagulation extent during in vivo percutaneous laser ablation of the liver. METHODS: A novel inertial acoustic driver was developed to apply mechanical waves via the ablation instrument. Ablation testing was performed in live juvenile female pigs under anesthesia in a 1.5-T whole-body MRI scanner. RESULTS: The inertial driver produced suitable mechanical wave fields in the liver before, during, and after the laser ablation. During 2-min ablations using 4.5-, 7.5- and 15-W laser power, the stiffness of the lesions changed substantially in response to laser heating, indicative of protein denaturation. After a lethal thermal dose (2-min, 15-W) ablation, lesion stiffness was significantly greater than the baseline values (P < 0.007) and became stiffer over time; the mean stiffness increments from baseline were significantly greater than those after lower dose (2-min, 7.5-W) ablations (64.4% vs. 22.5%, P = 0.009). CONCLUSION: MRE was shown capable of measuring tissue stiffness changes due to in vivo laser ablation. If confirmed through additional studies, this technology may be useful in clinical tumor ablation to monitor the spatial extent of tissue coagulation.

Preoperative assessment of meningioma stiffness using magnetic resonance elastography.

OBJECT: The object of this study was to determine the potential of magnetic resonance elastography (MRE) to preoperatively assess the stiffness of meningiomas. METHODS: Thirteen patients with meningiomas underwent 3D brain MRE examination to measure stiffness in the tumor as well as in surrounding brain tissue. Blinded to the MRE results, neurosurgeons made a qualitative assessment of tumor stiffness at the time of resection. The ability of MRE to predict the surgical assessment of stiffness was tested using a Spearman rank correlation. RESULTS: One case was excluded due to a small tumor size. In the remaining 12 cases, both tumor stiffness alone (p = 0.023) and the ratio of tumor stiffness to surrounding brain tissue stiffness (p = 0.0032) significantly correlated with the surgeons' qualitative assessment of tumor stiffness. Results of the MRE examination provided a stronger correlation with the surgical assessment of stiffness compared with traditional T1- and T2-weighted imaging (p = 0.089), particularly when considering meningiomas of intermediate stiffness. CONCLUSIONS: In this cohort, preoperative MRE predicted tumor consistency at the time of surgery. Tumor stiffness as measured using MRE outperformed conventional MRI because tumor appearance on T1- and T2-weighted images could only accurately predict the softest and hardest meningiomas.

Assessment of stiffness changes in the ex vivo porcine aortic wall using magnetic resonance elastography.

Magnetic resonance elastography (MRE) is a noninvasive phase-contrast technique for estimating the mechanical properties of tissues by imaging propagating mechanical waves within the tissue. In this study, we hypothesize that changes in arterial wall stiffness, experimentally induced by formalin fixation, can be measured using MRE in ex vivo porcine aortas. In agreement with our hypothesis, the significant stiffness increase after sample fixation was clearly demonstrated by MRE and confirmed by mechanical testing. The results indicate that MRE can be used to examine the stiffness changes of the aorta. This study has provided evidence of the effectiveness of using MRE to directly assess the stiffness change in aortic wall. The results offer motivation to pursue MRE as a noninvasive method for the evaluation of arterial wall mechanical properties.

Noninvasive In vivo assessment of renal tissue elasticity during graded renal ischemia using MR elastography.

OBJECTIVES: : Magnetic resonance elastography (MRE) allows noninvasive assessment of tissue stiffness in vivo. Renal arterial stenosis (RAS), a narrowing of the renal artery, promotes irreversible tissue fibrosis that threatens kidney viability and may elevate tissue stiffness. However, kidney stiffness may also be affected by hemodynamic factors. This study tested the hypothesis that renal blood flow (RBF) is an important determinant of renal stiffness as measured by MRE. MATERIAL AND METHODS: : In 6 anesthetized pigs MRE studies were performed to determine cortical and medullary elasticity during acute graded decreases in RBF (by 20%, 40%, 60%, 80%, and 100% of baseline) achieved by a vascular occluder. Three sham-operated swine served as time control. Additional pigs were studied with MRE 6 weeks after induction of chronic unilateral RAS (n = 6) or control (n = 3). Kidney fibrosis was subsequently evaluated histologically by trichrome staining. RESULTS: : During acute RAS the stenotic cortex stiffness decreased (from 7.4 ± 0.3 to 4.8 ± 0.6 kPa, P = 0.02 vs. baseline) as RBF decreased. Furthermore, in pigs with chronic RAS (80% ± 5.4% stenosis) in which RBF was decreased by 60% ± 14% compared with controls, cortical stiffness was not significantly different from normal (7.4 ± 0.3 vs. 7.6 ± 0.3 kPa, P = 0.3), despite histologic evidence of renal tissue fibrosis. CONCLUSION: : Hemodynamic variables modulate kidney stiffness measured by MRE and may mask the presence of fibrosis. These results suggest that kidney turgor should be considered during interpretation of elasticity assessments.

MR elastography as a method for the assessment of myocardial stiffness: comparison with an established pressure-volume model in a left ventricular model of the heart.

Magnetic resonance elastography (MRE) measurements of shear stiffness (mu) in a spherical phantom experiencing both static and cyclic pressure variations were compared to those derived from an established pressure-volume (P-V)-based model. A spherical phantom was constructed using a silicone rubber composite of 10 cm inner diameter and 1.3 cm thickness. A gradient echo MRE sequence was used to determine mu within the phantom at static and cyclic pressures ranging from 55 to 90 mmHg. Average values of mu using MRE were obtained within a region of interest and were compared to the P-V-derived estimates. Under both static and cyclic pressure conditions, the P-V- and MRE-based estimates of mu ranged from 98.2 to 155.1 kPa and 96.2 to 150.8 kPa, respectively. Correlation coefficients (R(2)) of 0.98 and 0.97 between the P-V and MRE-based estimates of shear stiffness measurements were obtained. For both static and cyclic pressures, MRE-based measures of mu agree with those derived from a P-V model, suggesting that MRE can be used as a new, noninvasive method of assessing mu in sphere-like fluid-filled organs such as the heart.

Assessment of hepatic fibrosis with magnetic resonance elastography.

BACKGROUND & AIMS: Accurate detection of hepatic fibrosis is crucial for assessing prognosis and candidacy for treatment in patients with chronic liver disease. Magnetic resonance (MR) elastography, a technique for quantitatively assessing the mechanical properties of soft tissues, has been shown previously to have potential for noninvasively detecting liver fibrosis. The goal of this work was to obtain preliminary estimates of the sensitivity and specificity of the technique in diagnosing liver fibrosis, and to assess its potential for identifying patients who potentially can avoid a biopsy procedure. METHODS: MR elastography was performed in 35 normal volunteers and 50 patients with chronic liver disease. MR imaging measurements of hepatic fat to water ratios were obtained to assess the potential for fat infiltration to affect stiffness-based detection of fibrosis. RESULTS: Liver stiffness increased systematically with fibrosis stage. Receiver operating curve analysis showed that, with a shear stiffness cut-off value of 2.93 kilopascals, the predicted sensitivity and specificity for detecting all grades of liver fibrosis is 98% and 99%, respectively. Receiver operating curve analysis also provided evidence that MR elastography can discriminate between patients with moderate and severe fibrosis (grades 2-4) and those with mild fibrosis (sensitivity, 86%; specificity, 85%). Hepatic stiffness does not appear to be influenced by the degree of steatosis. CONCLUSIONS: MR elastography is a safe, noninvasive technique with excellent diagnostic accuracy for assessing hepatic fibrosis. Based on the high negative predictive value of MR elastography, an initial clinical application may be to triage patients who are under consideration for biopsy examination to assess possible hepatic fibrosis.

Preliminary assessment of one-dimensional MR elastography for use in monitoring focused ultrasound therapy.

The purpose of this work is to assess a fast technique that measures tissue stiffness and temperature during focused ultrasound thermal therapy (FUS). A one-dimensional (1D) MR elastography (MRE) pulse sequence was evaluated for the purpose of obtaining rapid measurements of thermally induced changes in tissue stiffness and temperature for monitoring FUS treatments. The accuracy of the 1D measurement was studied by comparing tissue displacements measured by 1D MRE with those measured by the well-established 2D MRE pulse sequence. The reproducibility of the 1D MRE measurement was assessed, in gel phantoms and ex vivo porcine tissue, for varied FUS intensity levels (31.5-199.9 W cm(-2)) and over a range of displacements at the focus (0.1-1 microm). Temperature elevations in agarose gel phantoms were measured using 1D MRE and calibrated using fiberoptic-thermometer-based measurements. The 1D MRE displacement measurements are highly correlated with those obtained with the 2D technique (R(2) = 0.88-0.93), indicating that 1D MRE can successfully measure tissue displacement. Ten repeated trials at each FUS power level yielded a minimum detectable displacement change of 0.2 microm in phantoms and 0.4 microm in tissue (at 95% confidence level). The 1D MRE temperature measurements correlated well with temperature changes measured simultaneously with fiberoptic thermometers (R(2) = 0.97). The 1D MRE technique is capable of detecting tissue displacements as low as 0.4 microm, which is an order of magnitude smaller than 5 microm displacements expected during FUS therapy (Le et al 2005 AIP Conf. Proc.: Ther. Ultrasound 829 186-90). Additionally, 1D MRE was shown to provide adequate measurements of temperature elevations in tissue. These findings indicate that 1D MRE may be an effective tool for monitoring FUS treatments.

Quantitative assessment of hepatic fibrosis in an animal model with magnetic resonance elastography.

Chronic liver disease is a world-wide problem that causes progressive hepatic fibrosis as a hallmark of progressive injury. At present, the gold standard for diagnosing hepatic fibrosis is liver biopsy, which is an invasive method with many limitations, including questionable accuracy and risks of complications. MR elastography (MRE), a phase-contrast MRI technique for quantitatively assessing the mechanical properties of soft tissues, is a potential noninvasive diagnostic method to assess hepatic fibrosis. In this work, MRE was evaluated as a quantitative method to assess the in vivo mechanical properties of the liver tissues in a knockout animal model of liver fibrosis. This work demonstrates that the shear stiffness of liver tissue increases systematically with the extent of hepatic fibrosis, as measured by histology. A linear correlation between liver stiffness and fibrosis extent was well-defined in this animal model. An additional finding of the study was that fat infiltration, commonly present in chronic liver disease, does not significantly correlate with liver stiffness at each fibrosis stage and thus does not appear to interfere with the ability of MRE to assess fibrosis extent. In conclusion, MRE has the potential not only for assessing liver stiffness, but also for monitoring potential therapies for hepatic fibrosis.