Josephine H. Naish

Comprehensive Validation of Cardiovascular Magnetic Resonance Techniques for the Assessment of Myocardial Extracellular Volume

Background— Extracellular matrix expansion is a key element of ventricular remodeling and a potential therapeutic target. Cardiovascular magnetic resonance (CMR) T1-mapping techniques are increasingly used to evaluate myocardial extracellular volume (ECV); however, the most widely applied methods are without histological validation. Our aim was to perform comprehensive validation of (1) dynamic-equilibrium CMR (DynEq-CMR), where ECV is quantified using hematocrit-adjusted myocardial and blood T1 values measured before and after gadolinium bolus; and (2) isolated measurement of myocardial T1, used as an ECV surrogate. Methods and Results— Whole-heart histological validation was performed using 96 tissue samples, analyzed for picrosirius red collagen volume fraction, obtained from each of 16 segments of the explanted hearts of 6 patients undergoing heart transplantation who had prospectively undergone CMR before transplantation (median interval between CMR and transplantation, 29 days). DynEq-CMR–derived ECV was calculated from T1 measurements made using a modified Look-Locker inversion recovery sequence before and 10 and 15 minutes post contrast. In addition, ECV was measured 2 to 20 minutes post contrast in 30 healthy volunteers. There was a strong linear relationship between DynEq-CMR–derived ECV and histological collagen volume fraction (P<0.001; within-subject: r=0.745; P<0.001; r 2=0.555 and between-subject: r=0.945; P<0.01; r 2=0.893; for ECV calculated using 15-minute postcontrast T1). Correlation was maintained throughout the entire heart. Isolated postcontrast T1 measurement showed significant within-subject correlation with histological collagen volume fraction (r=−0.741; P<0.001; r 2=0.550 for 15-minute postcontrast T1), but between-subject correlations were not significant. DynEq-CMR–derived ECV varied significantly according to contrast dose, myocardial region, and sex. Conclusions— DynEq-CMR–derived ECV shows a good correlation with histological collagen volume fraction throughout the whole heart. Isolated postcontrast T1 measurement is insufficient for ECV assessment.

Preliminary Study of Oxygen-Enhanced Longitudinal Relaxation in MRI: A Potential Novel Biomarker of Oxygenation Changes in Solid Tumors

PURPOSE There is considerable interest in developing non-invasive methods of mapping tumor hypoxia. Changes in tissue oxygen concentration produce proportional changes in the magnetic resonance imaging (MRI) longitudinal relaxation rate (R(1)). This technique has been used previously to evaluate oxygen delivery to healthy tissues and is distinct from blood oxygenation level-dependent (BOLD) imaging. Here we report application of this method to detect alteration in tumor oxygenation status. METHODS AND MATERIALS Ten patients with advanced cancer of the abdomen and pelvis underwent serial measurement of tumor R(1) while breathing medical air (21% oxygen) followed by 100% oxygen (oxygen-enhanced MRI). Gadolinium-based dynamic contrast-enhanced MRI was then performed to compare the spatial distribution of perfusion with that of oxygen-induced DeltaR(1). RESULTS DeltaR(1) showed significant increases of 0.021 to 0.058 s(-1) in eight patients with either locally recurrent tumor from cervical and hepatocellular carcinomas or metastases from ovarian and colorectal carcinomas. In general, there was congruency between perfusion and oxygen concentration. However, regional mismatch was observed in some tumor cores. Here, moderate gadolinium uptake (consistent with moderate perfusion) was associated with low area under the DeltaR(1) curve (consistent with minimal increase in oxygen concentration). CONCLUSIONS These results provide evidence that oxygen-enhanced longitudinal relaxation can monitor changes in tumor oxygen concentration. The technique shows promise in identifying hypoxic regions within tumors and may enable spatial mapping of change in tumor oxygen concentration.

Comparison of normal tissue R1 and R *2 modulation by oxygen and carbogen

Magnetic resonance imaging has shown promise for evaluating tissue oxygenation. In this study differences in the tissue longitudinal relaxation rate (R1) and effective transverse relaxation rate (R  *2 ), induced by inhalation of pure oxygen and carbogen, were evaluated in 10 healthy subjects. Significant reductions in R1 were demonstrated following both oxygen and carbogen inhalation in the spleen (both P < 0.001), liver (P = 0.002 air vs. oxygen; P = 0.001 air vs. carbogen), skeletal muscle (both P < 0.001), and renal cortex (P = 0.005 air vs. oxygen; P = 0.008 air vs. carbogen). No significant change in R  *2 occurred following pure oxygen in any organ. However, a significant increase in R  *2 was observed in the spleen (P < 0.001), liver (P = 0.001), skeletal muscle (P = 0.026), and renal cortex (P = 0.001) following carbogen inhalation, an opposite effect to that observed in many studies of tumor pathophysiology. Changes in R1 and R  *2 were independent of the gas administration order in the spleen and skeletal muscle. These findings suggest that the R1 and R  *2 responses to hyperoxic gases are independent biomarkers of oxygen physiology. Magn Reson Med 61:75–83, 2009.

Organ-specific effects of oxygen and carbogen gas inhalation on tissue longitudinal relaxation times.

Molecular oxygen has been previously shown to shorten longitudinal relaxation time (T1) in the spleen and renal cortex, but not in the liver or fat. In this study, the magnitude and temporal evolution of this effect were investigated. Medical air, oxygen, and carbogen (95% oxygen/5% CO2) were administered sequentially in 16 healthy volunteers. T1 maps were acquired using spoiled gradient echo sequences (TR = 3.5 ms, TE = 0.9 ms, α = 2°/8°/17°) with six acquisitions on air, 12 on oxygen, 12 on carbogen, and six to 12 back on air. Mean T1 values and change in relaxation rate were compared between each phase of gas inhalation in the liver, spleen, skeletal muscle, renal cortex, and fat by one‐way analysis of variance. Oxygen‐induced T1‐shortening occurred in the liver in fasted subjects (P < 0.001) but not in non‐fasted subjects (P = 0.244). T1‐shortening in spleen and renal cortex (both P < 0.001) were greater than previously reported. Carbogen induced conflicting responses in different organs, suggesting a complex relationship with organ vasculature. Shortening of tissue T1 by oxygen is more pronounced and more complex than previously recognized. The effect may be useful as a biomarker of arterial flow and oxygen delivery to vascular beds. Magn Reson Med 58:490–496, 2007.

Modeling of contrast agent kinetics in the lung using T1-weighted dynamic contrast-enhanced MRI

Assessment of perfusion and capillary permeability is important in both malignant and nonmalignant lung disease. Kinetic modeling of T1‐weighted dynamic contrast‐enhanced MRI (DCE‐MRI) data may provide such an assessment. This study establishes the feasibility and interrelationship of kinetic modeling approaches designed to estimate microvascular properties in malignant and nonmalignant tissues of the lung. DCE‐MRI data were acquired using a low molecular weight contrast agent with 4‐sec temporal resolution in lung cancer patients. A model‐free parameterization and three kinetic models of increasing complexity, each related to the classical Kety model, were applied. Comparison of an extended Kety model and the adiabatic approximation to the tissue homogeneity (AATH) model using Akaikes Information Criterion suggested that in most cases the best description of the lung tumor data is obtained using the AATH model. In the normal lung parenchyma the temporal resolution was insufficient to separate effects of flow and contrast agent leakage and in this case the extended Kety model yielded the best fit to the data. Magn Reson Med, 2009.

Improved quantitative dynamic regional oxygen-enhanced pulmonary imaging using image registration

Oxygen‐enhanced MR imaging has been demonstrated in a number of recent studies as a potential method to visualize regional ventilation in the lung. A quantitative pixel‐by‐pixel analysis is hampered by motion and volume change due to breathing. In this study, image registration via active shape modeling is shown to produce significant improvements in the regional analysis of both static and dynamic oxygen‐enhanced pulmonary MRI for five normal volunteers. The method enables the calculation of regional change in relaxation rate between breathing air and 100% oxygen, which is proportional to the change in regional oxygen concentration, and regional oxygen wash‐in and wash‐out time constants. Registration‐corrected mapping of these parameters is likely to provide improved information in the regional assessment of a range of lung diseases. Magn Reson Med 54:464–469, 2005.

R1 and R2* changes in the human placenta in response to maternal oxygen challenge

Pregnancy complications such as preeclampsia and fetal growth restriction are sometimes thought to be caused by placental abnormalities associated with reduced oxygenation. Oxygen‐enhanced MRI (R1 contrast) and BOLD MRI (R2* contrast) have the potential to noninvasively investigate this oxygen environment at a range of gestational ages.

Tracer kinetic analysis of dynamic contrast‐enhanced MRI and CT bladder cancer data: A preliminary comparison to assess the magnitude of water exchange effects

The purpose of this study was to determine the impact of water exchange on tracer kinetic parameter estimates derived from T1‐weighted dynamic contrast‐enhanced (DCE)‐MRI data using a direct quantitative comparison with DCE‐CT. Data were acquired from 12 patients with bladder cancer who underwent DCE‐CT followed by DCE‐MRI within a week. A two‐compartment tracer kinetic model was fitted to the CT data, and two versions of the same model with modifications to account for the fast exchange and no exchange limits of water exchange were fitted to the MR data. The two‐compartment tracer kinetic model provided estimates of the fractional plasma volume (vp), the extravascular extracellular space fraction (ve), plasma perfusion (Fp), and the microvascular permeability surface area product. Our findings suggest that DCE‐CT is an appropriate reference for DCE‐MRI in bladder cancers as the only significant difference found between CT and MR parameter estimates were the no exchange limit estimates of vp (P = 0.002). These results suggest that although water exchange between the intracellular and extravascular‐extracellular space has a negligible effect on DCE‐MRI, vascular–extravascular‐extracellular space water exchange may be more important. Magn Reson Med, 2010.

Noninvasive tumor hypoxia measurement using magnetic resonance imaging in murine U87 glioma xenografts and in patients with glioblastoma.

There is a clinical need for noninvasive, nonionizing imaging biomarkers of tumor hypoxia and oxygenation. We evaluated the relationship of T1‐weighted oxygen‐enhanced magnetic resonance imaging (OE‐MRI) measurements to histopathology measurements of tumor hypoxia in a murine glioma xenograft and demonstrated technique translation in human glioblastoma multiforme.

Non-invasive tumor hypoxia measurement using magnetic resonance imaging in mouse and human glioblastoma

There is a clinical need for noninvasive, nonionizing imaging biomarkers of tumor hypoxia and oxygenation. We evaluated the relationship of T1‐weighted oxygen‐enhanced magnetic resonance imaging (OE‐MRI) measurements to histopathology measurements of tumor hypoxia in a murine glioma xenograft and demonstrated technique translation in human glioblastoma multiforme.