Regional contrast agent quantification in a mouse model of myocardial infarction using 3D cardiac T1 mapping

<p>Abstract</p> <p>Background</p> <p>Quantitative relaxation time measurements by cardiovascular magnetic resonance (CMR) are of paramount importance in contrast-enhanced studies of experimental myocardial infarction. First, compared to qualitative measurements based on signal intensity changes, they are less sensitive to specific parameter choices, thereby allowing for better comparison between different studies or during longitudinal studies. Secondly, T₁measurements may allow for quantification of local contrast agent concentrations. In this study, a recently developed 3D T₁mapping technique was applied in a mouse model of myocardial infarction to measure differences in myocardial T₁before and after injection of a liposomal contrast agent. This was then used to assess the concentration of accumulated contrast agent.</p> <p>Materials and methods</p> <p>Myocardial ischemia/reperfusion injury was induced in 8 mice by transient ligation of the LAD coronary artery. Baseline quantitative T₁maps were made at day 1 after surgery, followed by injection of a Gd-based liposomal contrast agent. Five mice served as control group, which followed the same protocol without initial surgery. Twenty-four hours post-injection, a second T₁measurement was performed. Local ΔR₁values were compared with regional wall thickening determined by functional cine CMR and correlated to <it>ex vivo </it>Gd concentrations determined by ICP-MS.</p> <p>Results</p> <p>Compared to control values, pre-contrast T₁of infarcted myocardium was slightly elevated, whereas T₁of remote myocardium did not significantly differ. Twenty-four hours post-contrast injection, high ΔR₁values were found in regions with low wall thickening values. However, compared to remote tissue (wall thickening > 45%), ΔR₁was only significantly higher in severe infarcted tissue (wall thickening < 15%). A substantial correlation (<it>r </it>= 0.81) was found between CMR-based ΔR₁values and Gd concentrations from <it>ex vivo </it>ICP-MS measurements. Furthermore, regression analysis revealed that the effective relaxivity of the liposomal contrast agent was only about half the value determined <it>in vitro</it>.</p> <p>Conclusions</p> <p>3D cardiac T₁mapping by CMR can be used to monitor the accumulation of contrast agents in contrast-enhanced studies of murine myocardial infarction. The contrast agent relaxivity was decreased under <it>in vivo </it>conditions compared to <it>in vitro </it>measurements, which needs consideration when quantifying local contrast agent concentrations.</p

Myocardial perfusion MRI shows impaired perfusion of the mouse hypertrophic left ventricle

There is growing consensus that myocardial perfusion deficits play a pivotal role in the transition from compensated to overt decompensated hypertrophy. The purpose of this study was to systematically study myocardial perfusion deficits in the highly relevant model of pressure overload induced hypertrophy and heart failur

Novel strategies for mouse cardiac MRI - Better Stronger Faster

Mouse models of cardiac disease are an important tool to gain understanding of the pathophysiological processes related to the heart, as well as for the development of new treatment strategies. In this respect, Magnetic Resonance Imaging (MRI) has become the gold standard imaging modality, because it combines high spatial resolution imaging with a large variety of soft tissue contrast weightings that can be related to the presence of diseased tissue. In addition, (targeted) MRI contrast agents can be employed to visualize different processes on the molecular level, for example in relation to myocardial infarction and the subsequent cardiac remodeling process. The specificity to discriminate healthy from diseased tissue as well as the sensitivity for detection of MR contrast agents is strongly affected by the specific MRI protocol design. Moreover, the challenging physiology of the mouse heart, especially with respect to its small size and high heart rate, often limits the direct translation of imaging protocols already available from clinical studies. Finally, the growing knowledge on cardiac pathology continuously pushes the development of sophisticated mouse cardiac MRI protocols that allow more detailed measurements of a variety of physiologically relevant cardiac parameters. The overall goal of this thesis was therefore to design and investigate novel imaging strategies in the field of mouse cardiac MRI and their application in models of cardiac disease. Chapter 2 of this thesis contains an extensive overview of currently available protocols for mouse cardiac MRI and more specifically those related to contrast enhanced imaging of myocardial infarction. The remainder of the thesis contains the experimental chapters describing all details on our newly developed mouse cardiac MRI techniques. This chapter shortly summarizes the aims and results with respect to each of these techniques, categorized based on the parameter of interest for which each measurement was specifically designed. Diastolic function Measurement of murine diastolic function requires Cine imaging with an extremely high frame rate ¿ more than 60 frames within a cardiac cycle of 100-120 ms ¿ to be able to discriminate between the two separate filling phases of the heart. In chapter 3, it was shown that using a retrospectively triggered MRI sequence, reconstruction of 80 Cine images was feasible, corresponding to a temporal resolution of around 1.5 ms. This was achieved without using any form of data interpolation. With retrospective triggering, the MRI measurements are not synchronized with the ECG, thereby in theory sampling an infinite number of time points during the cardiac cycle. Correct assignment of each k-line to a specific cardiac frame could be done retrospectively by measuring an additional navigator signal prior to image acquisition, whose signal amplitude varies with cardiac as well as respiratory movements. Because in this case, filling of k-space for each cardiac frame is a stochastic process, simulations were performed to investigate the efficiency of the method with respect to signal averaging, which was found to be almost equal compared to regular prospective triggering. Diabetic cardiomyopathy has a high prevalence in type 2 diabetes patients and is characterized by diastolic dysfunction. With the current technique, we were indeed able to measure a subtle reduction is several diastolic function parameters, which are the E/A-ratio and the E-contribution to total left ventricular filling. Therefore, this technique is a promising tool in experimental studies of diabetic cardiomyopathy and for evaluation of emerging treatment strategies for diastolic dysfunction. Myocardial perfusion Chapter 4 describes the application of first-pass perfusion measurements in a mouse model of myocardial infarction to allow the assessment of the myocardial perfusion status. A first-pass perfusion measurement is performed by venous injection of an MRI contrast agent and monitoring its passage through the left ventricle and myocardial wall. From the signal intensity changes upon passage of the contrast agent, myocardial perfusion values can be determined. The application of this technique in mice requires ultra-fast MRI sequences that can sample the signal intensity-time curves with sufficient temporal resolution. Because this concerns imaging of non-periodic signal changes this is a much different problem compared to the diastolic function experiments described in chapter 3. We showed that using a saturation recovery MRI sequence with segmented k-space read-out in combination with parallel imaging acceleration techniques, a time-series of images could be acquired with a temporal resolution of 1 image for each 3 heart beats. The use of parallel imaging was crucial, since this requires less k-lines for image reconstruction compared to conventional imaging. Furthermore, the use of saturation pulses enhanced the contrast between contrast-enhanced and non-enhanced blood and myocardium. Using this technique, semi-quantitative perfusion values could be determined based on the upslope of the signal intensity-time curves. Experiments in mice with permanent occlusion of the LAD showed a significant decrease of perfusion values in the infarcted myocardium as compared to remote myocardium. In future experiments, this technique will be extended to provide quantitative perfusion values (in mg/l/min), requiring determination of the true arterial input function from a pre-bolus measurement with a smaller contrast agent bolus volume. T1 and T2 relaxation times Pathology is often accompanied by a change in the magnetic properties of the tissue, in particular the T1 and T2 relaxation times. This directly affects the signal intensity on the MR image. Diseased and healthy tissue can therefore be discriminated on MR images, which is one of the main applications of MRI in clinical diagnostics. However, there is much interest in quantitative assesment of T1 and T2 relaxation times, as this improves repeatibility of results in longitudinal studies and reproducibility between research groups. In this thesis, we aimed at developing protocols for both T1 and T2 mapping of the complete mouse heart for application in mouse models of myocardial infarction. Whole-heart coverage is important considering that a priori, the extent of the infarct is unknown. Currently available protocols for T1 mapping are relatvively time-consuming. In chapter 5, a 3D T1 mapping sequence is presented which allows myocardial T1 quantification of the mouse heart within 20 minutes. The retrospective triggering sequence used in chapter 3 proved also useful in this study, because it allows steady-state acqusition with very short repetition times, enabling whole heart coverage. T1 values were derived from measuring a variable flip angle data set and using available MRI signal models. Variable flip angle data showed excellent agreement in cardiac anatomy, allowing pixel-wise determination of T1. In healthy mice, no substantial differences in T1 were found for different heart regions in the 3D volume. Coefficents of repeatibility were determined from measurements at different days, which varied as function of the number of flip angles used in data analysis. In contrast to T1, T2 values could not be acquired using 3D acquisitons or retrospective triggering. Alternatively, chapter 6 describes a multi-slice T2 mapping protocol for the mouse heart based on a ECG-triggered T2 magnetization preparation module with variable TE. Because the preparation module consisted of many consecutive RF pulses, the effect of these pulses on T2 relxation had to be taken into account. Additionally, simulations were used to calculate the effect of T1 relaxation on T2 estimation, which was small as long as the repetition time was kept sufficiently long. Homogeneous T2 maps of healthy mouse heart were obtained, with no substantial differences between different heart regions or slices. In a ischemia/reperfusion model, elevated T2 values were found in the infarcted area, probably as result of edema formation. The extent of the infarction was also measured using late gadolinium enhanced imaging. The degree of correlation of T2 and LGE enhanced regions strongly depended on the signal intensity thresholds derived from remote tissue. Contrast agent accumulation Another application of quantitative T1 and T2¬ mapping is the assessment of the concentration of a contrast agent, which has been targeted to a specific disease site. This is especially valuable in molecular imaging applications where contrast agents report on the presence of specific disease markers related to various cardiac remodeling processes after myocardial infarction. Chapter 7 describes the application of the T1 mapping protocol from chapter 5 to quantify the accumulation of a Gd-based liposomal contrast agent in a model of myocardial infarction. Functional imaging and assessment of wall thickening values were used to determine which regions could be identified as being infarcted. Statistical analysis showed that before contrast agent administration, T¬1¬ values were already elevated in the infarcted regions as compared to remote myocardium, however, a more pronounced change in T1 values was found 24h post-contrast, with significantly lower T1 values in the infarcted areas. Pre-contrast T1 values in control mice were very similar to the study described in chapter 5, proving good reproducibility of T1 quantification using our methods. After the MRI measurement, the hearts were cut into slices, from which the Gd-content was determined in different sections of the heart using inductively coupled plasma mass spectrometry. T1 changes measured using in vivo MRI correlated well with ex vivo measurements of Gd concentration. These are promising results for quantification of contrast agent concentrations in contrast-enhanced MRI of mouse models of cardiac disease. More research has to be performed with regard to changes in contrast agent efficiency as a result of different cellular environments. Our results already indicate that the relaxivity values of liposomal contrast agents are significantly lower in vivo as compared to values obtained from measurements in phantom solutions. Conclusion This thesis has shown that mouse cardiac MRI is capable of assessing a large variety of parameters related to cardiac physiology in the in vivo mouse heart in a non-invasive way. This makes this technique an attractive platform for experimental studies on cardiac disease, as well as developing new treatment strategies

Hymenophore configuration of the oak mazegill (Daedalea quercina)

The complex hymenophore configuration of the oak mazegill (Daedalea quercina, Polyporales) is rarely quantified, although quantifications are important analytical tools to assess form and growth. We quantified the hymenophore configuration of the oak mazegill by manual counting of tubes and tubular branches and ends. Complementary measurements were made with the software AngioTool. We found that the number of tubular branches and ends varied substantially between specimens, with a positive correlation with hymenophore area (5–51 cm2). We then measured complexity as tubular branches and ends per area, and complexity was not correlated with the size of the basidiocarps. Basidiocarps from two locations were compared (Hald ege, N = 11; Hvidding krat, N = 7), and the prevalence of branches and that of ends were greater in the Hvidding krat hymenophores (P < 0.001 and P = 0.029, respectively). Additionally, lacunarity, a measure of complexity (“gappiness”), gave a higher score for the Hald ege hymenophores (P = 0.002). Lacunarity analysis of multiple species of Polyporales showed that the oak mazegill hymenophore is comparatively complex. Concerning factors that affect hymenophore complexity of the oak mazegill, we observed that greater hymenophore complexity was associated with abrupt boundaries between growth zones on the pileus surface. Several years of monitoring documented that basidiocarps can remodel to gravitational changes and heal from damage. In conclusion, intra- and interspecies differences of hymenophore configuration can be quantified. In oak mazegill, hymenophore complexity is not dependent on size per se, although abrupt borders between growth zones are associated with increased complexity. Some of the variation between basidiocarps may reflect aspects of the ecology of the individual fungus

Design and evaluation of an MRI-ready, self-propelled needle for prostate interventions

Prostate cancer diagnosis and focal laser ablation treatment both require the insertion of a needle for biopsy and optical fibre positioning. Needle insertion in soft tissues may cause tissue motion and deformation, which can, in turn, result in tissue damage and needle positioning errors. In this study, we present a prototype system making use of a wasp-inspired (bioinspired) self-propelled needle, which is able to move forward with zero external push force, thereby avoiding large tissue motion and deformation. Additionally, the actuation system solely consists of 3D printed parts and is therefore safe to use inside a magnetic resonance imaging (MRI) system. The needle consists of six parallel 0.25-mm diameter Nitinol rods driven by the actuation system. In the prototype, the self-propelled motion is achieved by advancing one needle segment while retracting the others. The advancing needle segment has to overcome a cutting and friction force while the retracting needle segments experience a friction force in the opposite direction. The needle self-propels through the tissue when the friction force of the five retracting needle segments overcomes the sum of the friction and cutting forces of the advancing needle segment. We tested the performance of the prototype in ex vivo human prostate tissue inside a preclinical MRI system in terms of the slip ratio of the needle with respect to the prostate tissue. The results showed that the needle was visible in MR images and that the needle was able to self-propel through the tissue with a slip ratio in the range of 0.78-0.95. The prototype is a step toward self-propelled needles for MRI-guided transperineal laser ablation as a method to treat prostate cancer

Design and evaluation of an MRI-ready, self-propelled needle for prostate interventions

Prostate cancer diagnosis and focal laser ablation treatment both require the insertion of a needle for biopsy and optical fibre positioning. Needle insertion in soft tissues may cause tissue motion and deformation, which can, in turn, result in tissue damage and needle positioning errors. In this study, we present a prototype system making use of a wasp-inspired (bioinspired) self-propelled needle, which is able to move forward with zero external push force, thereby avoiding large tissue motion and deformation. Additionally, the actuation system solely consists of 3D printed parts and is therefore safe to use inside a magnetic resonance imaging (MRI) system. The needle consists of six parallel 0.25-mm diameter Nitinol rods driven by the actuation system. In the prototype, the self-propelled motion is achieved by advancing one needle segment while retracting the others. The advancing needle segment has to overcome a cutting and friction force while the retracting needle segments experience a friction force in the opposite direction. The needle self-propels through the tissue when the friction force of the five retracting needle segments overcomes the sum of the friction and cutting forces of the advancing needle segment. We tested the performance of the prototype in ex vivo human prostate tissue inside a preclinical MRI system in terms of the slip ratio of the needle with respect to the prostate tissue. The results showed that the needle was visible in MR images and that the needle was able to self-propel through the tissue with a slip ratio in the range of 0.78–0.95. The prototype is a step toward self-propelled needles for MRI-guided transperineal laser ablation as a method to treat prostate cancer.Medical Instruments & Bio-Inspired Technolog

Three-dimensional Diffusion Imaging with SPiral Encoded Navigators from Stimulated Echoes (3D-DISPENSE)

Purpose: To introduce a new method for motion-insensitive 3D multishot diffusion imaging using 3D spiral-encoded navigators from stimulated echoes (3D-DISPENSE). Methods: The 3D-DISPENSE sequence contains a 3D stack-of-spiral navigator generated between the diffusion preparation and the turbo spin-echo image acquisition from the twin pathway of a stimulated echo. Unlike normal navigator methods, 3D-DISPENSE separates the navigator acquisition from the imaging readout without compromising the image SNR. Phase information from the navigators was included in an iterative image reconstruction algorithm to correct for intershot phase incoherence caused by motion. Results: In a phantom experiment, 3D-DISPENSE correctly estimated deliberately introduced phase errors. In a moving phantom, motion-induced artifacts in the DWI were greatly mitigated by 3D-DISPENSE. The ADC after 3D-DISPENSE correction was identical to the reference. In a brain diffusion tensor experiment, phase-incoherence artifacts from breathing, cardiac, and subject motion were removed almost perfectly in all view angles, resulting in distortion-free DWI and color-coded fractional anisotropy maps with 1.5-mm isotropic resolution and nearly full brain coverage. Conclusion: Three-dimensional DISPENSE corrects motion-induced phase-incoherence artifacts in 3D multishot diffusion imaging and produces high-quality 3D DWI and DTI

Compressed sensing MRI with variable density averaging (CS-VDA) outperforms full sampling at low SNR

We investigated whether a combination of k-space undersampling and variable density averaging enhances image quality for low-SNR MRI acquisitions. We implemented 3D Cartesian k-space prospective undersampling with a variable number of averages for each k-line. The performance of this compressed sensing with variable-density averaging (CS-VDA) method was evaluated in retrospective analysis of fully sampled phantom MRI measurements, as well as for prospectively accelerated in vivo 3D brain and knee MRI scans. Both phantom and in vivo results showed that acquisitions using the CS-VDA approach resulted in better image quality as compared to full sampling of k-space in the same scan time. Specifically, CS-VDA with a higher number of averages in the center of k-space resulted in the best image quality, apparent from increased anatomical detail with preserved soft-tissue contrast. This novel approach will facilitate improved image quality of inherently low SNR data, such as those with high-resolution or specific contrast-weightings with low SNR efficiency