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

From Molecules to Imaging: Assessment of Placental Hypoxia Biomarkers in Placental Insufficiency Syndromes

Placental hypoxia poses significant risks to both the developing fetus and the mother during pregnancy, underscoring the importance of early detection and monitoring. Effectively identifying placental hypoxia and evaluating the deterioration in placental function requires reliable biomarkers. Molecular biomarkers in placental tissue can only be determined post-delivery and while maternal blood biomarkers can be measured over time, they can merely serve as proxies for placental function. Therefore, there is an increasing demand for non-invasive imaging techniques capable of directly assessing the placental condition over time. Recent advancements in imaging technologies, including photoacoustic and magnetic resonance imaging, offer promising tools for detecting and monitoring placental hypoxia. Integrating molecular and imaging biomarkers may revolutionize the detection and monitoring of placental hypoxia, improving pregnancy outcomes and reducing long-term health complications. This review describes current research on molecular and imaging biomarkers of placental hypoxia both in human and animal studies and aims to explore the benefits of an integrated approach throughout gestation

A 3-slice cardiac quantitative native and post-contrast T1 and T2 MRI protocol requiring only four BHs using a 72-channel receive array coil

Introduction: Current practice to obtain left ventricular (LV) native and post-contrast T1 and T2 comprises single-slice readouts with multiple breath-holds (BHs). We propose a multi-slice parallel-imaging approach with a 72-channel receive-array to reduce BHs and demonstrate this in healthy subjects and hypertrophic cardiomyopathy (HCM) patients. Methods: A T1/T2 phantom was scanned at 3 T using a 16-channel and a novel 72-channel coil to assess the impact of different coils and acceleration factors on relaxation times. 16–18 healthy participants (8 female, age 28.4 ± 5.1 years) and 3 HCM patients (3 male, age 55.3 ± 4.2 years) underwent cardiac-MRI with the 72-channel coil, using a Modified Look-Locker scan with a shared inversion pulse across 3 slices and a Gradient-Spin-Echo scan. Acceleration was done by sensitivity encoding (SENSE) with accelerations 2, 4, and 6. LV T1 and T2 values were analyzed globally, per slice, and in 16 segments, with SENSE = 2 as the reference. Results: The phantom scans revealed no bias between coils and acceleration factors for T1 or T2, except for T2 with SENSE = 2, which resulted in a bias of 8.0 ± 6.7 ms (p < 0.001) between coils. SENSE = 4 and 6 enabled T1 mapping of three slices in a single BH, and T2 mapping of three slices within two BHs. In healthy subjects, T1 and T2 values varied. We found an average overestimation of T1 in 3 slices of 25 ± 87 ms for SENSE = 4 and 30 ± 103 ms using SENSE = 6, as compared to SENSE = 2. Acceleration resulted in decreased signal-to-noise; however, visually insignificant and without increased incidence of SENSE-artifacts. T2 was overestimated by 2.1 ± 5.0 ms for SENSE = 4 and 6.4 ± 9.7 ms using SENSE = 6, as compared to SENSE = 2. Native and post-contrast T1 measurements with SENSE = 4 and ECV quantification in HCM patients was successful. Conclusion: The 72-channel receiver-array coil with SENSE = 4 and 6, enabled LV-tissue characterization in three slices. Pre- and post-contrast T1 maps were obtained in a single BH, while T2 required two BHs

Assessment of feto-placental oxygenation and perfusion in a rat model of placental insufficiency using T2* mapping and 3D dynamic contrast-enhanced MRI

Introduction: Placental insufficiency may lead to preeclampsia and fetal growth restriction. There is no cure for placental insufficiency, emphasizing the need for monitoring fetal and placenta health. Current monitoring methods are limited, underscoring the necessity for imaging techniques to evaluate fetal-placental perfusion and oxygenation. This study aims to use MRI to evaluate placental oxygenation and perfusion in the reduced uterine perfusion pressure (RUPP) model of placental insufficiency. Methods: Pregnant rats were randomized to RUPP (n = 11) or sham surgery (n = 8) on gestational day 14. On gestational day 19, rats imaged using a 7T MRI scanner to assess oxygenation and perfusion using T2* mapping and 3D-DCE MRI sequences, respectively. The effect of the RUPP on the feto-placental units were analyzed from the MRI images. Results: RUPP surgery led to reduced oxygenation in the labyrinth (24.7 ± 1.8 ms vs. 28.0 ± 2.1 ms, P = 0.002) and junctional zone (7.0 ± 0.9 ms vs. 8.1 ± 1.1 ms, P = 0.04) of the placenta, as indicated by decreased T2* values. However, here were no significant differences in fetal organ oxygenation or placental perfusion between RUPP and sham animals. Discussion: The reduced placental oxygenation without a corresponding decrease in perfusion suggests an adaptive response to placental ischemia. While acute reduction in placental perfusion may cause placental hypoxia, persistence of this condition could indicate chronic placental insufficiency after ischemic reperfusion injury. Thus, placental oxygenation may be a more reliable biomarker for assessing fetal condition than perfusion in hypertensive disorders of pregnancies including preeclampsia and FGR

A consensus protocol for functional connectivity analysis in the rat brain

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows for comparisons with data modalities collected under invasive or terminal procedures. Currently, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. Here we introduce StandardRat, a consensus rat functional magnetic resonance imaging acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired from rats across 46 centers. We developed a reproducible pipeline for analyzing rat data acquired with diverse protocols and determined experimental and processing parameters associated with the robust detection of functional connectivity across centers. We show that the standardized protocol enhances biologically plausible functional connectivity patterns relative to previous acquisitions. The protocol and processing pipeline described here is openly shared with the neuroimaging community to promote interoperability and cooperation toward tackling the most important challenges in neuroscience

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

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