Admittance measurement for early detection of congestive heart failure

textImpedance has been used as a tool for cardiac research since the early 1940’s. Recently there have been many advances in this field in the diagnosis of human heart failure through the measurement of pacemaker and ICD coupled impedance detection to determine the state of pulmonary edema in patients through drops in lung impedance. These new detection methods are far downstream of the initial changes in physiology, which signify heart failure risk, namely, an increased left ventricular (LV) end-diastolic volume (also known as preload). This dissertation presents the first formal validation of the complex admittance technique for more accurate blood volume measurement in vivo in mice. It aims to determine a new configuration of admittance measurement in a large scale animal model (pigs). It also aims to prove that “piggybacking” an admittance measurement system onto previously implanted AICD and bi-ventricular pacemakers is a feasible and practical measurement that will serve as an early warning system for impending heart failure through the measurement of LV preload, which appears before the currently measured drop in lung impedance using previous techniques.Electrical and Computer Engineerin

Applications of Rapid Cardiac Micro-CT

Mouse models are an important tool in cardiovascular disease research and a non-invasive imaging method is an advantageous way of monitoring disease progression. Cardiac micro-CT is rapid imaging technique capable of quantifying changes in cardiac structure and function in mice. The goal of this thesis was to demonstrate the utility of this technique in monitoring disease progression in a longitudinal study, as well as its capability for evaluating other methods of measuring cardiac function in mice. In a longitudinal study, a mouse model of myocardial infarction was scanned weekly for four weeks; left ventricular volume and ejection fraction were measured from the images. Cardiac micro-CT was capable of tracking small changes in cardiac structure and function, with the MI mice demonstrating a significant increase in volume and a significant decrease in ejection fraction. Both inter- and intra-variability was low, indicating the results were highly reproducible. Contrast agents are essential to evaluating the heart in micro-CT images. A new blood-pool agent was evaluated to determine its suitability for use in cardiac micro-CT studies. The agent produced excellent enhancement for the first 30 minutes post-injection, and had a unique characteristic of enhancing the myocardium, which may prove useful in studies evaluating wall motion. The effect of x-ray dose delivered during a longitudinal micro-CT study was also evaluated. C57BL/6 mice were scanned weekly for six weeks; the total entrance dose delivered over the study was 5.04 Gy. No significant changes to the heart or lungs were detectable on the micro-CT images at six weeks, and the histology performed on myocardial and pulmonary tissue showed no indication of early inflammation at a cellular level. Micro-CT can therefore be used in longitudinal studies without concern of adverse effects. Cardiac micro-CT was used to evaluate conductance catheters, and found that the catheter volumes were drastically underestimated compared to the micro-CT volumes. It was also determined that catheterization has the potential for causing cardiac enlargement; 40% of the mice demonstrated enlarged hearts following the catheterization procedure. Overall, cardiac-gated micro-CT is a rapid and reproducible imaging technique, and is proving to be valuable tool in cardiovascular disease research

Speckle-Tracking Imaging, Principles and Clinical Applications: A Review for Clinical Cardiologists

Evaluation of myocardial mechanics, although complex, has now entered the clinical arena, thanks to the introduction of bedside imaging techniques, such as speckle-tracking echocardiography

Das regenerative Potential der CD117+AT2R stimulierten Zellpopulation in vitro und in vivo

Regarding innovative therapeutical approaches for cardiac regeneration, we thoroughly investigated CD117+ and CD117+AT2R stimulated murine bone marrow stem cells. Electrophysiological measurements and in vitro results indicated the differentiation into an endothelial-like phenotype excluding a previously discussed development into cardiomyocytes. Cell implantation into infarcted murine heart provoked a significant improvement of cardiac function. AT2R triggered effects were not significantly different and should be analyzed in interplay with its opposing receptor AT1

Novel strategies for mouse cardiac MRI : better, faster, stronger

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

Video Kinematic Evaluation: new insights on the cardiac mechanical function

The cardiac mechanical function plays a critical role in governing and regulating its performance under both normal and pathological conditions. The left ventricle has historically received more attention in both congenital and acquired heart diseases and was considered as the mainstay of normal hemodynamics. However, over the past few decades, there has been increasing recognition of the pivotal role of the right ventricle in determining functional performance status and prognosis in multiple conditions. Nonetheless, the ventricles should not be considered separately as they share the septum, are encircled with common myocardial fibers and are surrounded by the pericardium. Thus, changes in the filling of one ventricle may alter the mechanical function of its counterpart. This ventricular interdependence remains even after the removal of the pericardium because of constrictive pericarditis or during open chest surgery. Interestingly, during open chest surgery, only the right ventricle mechanical activity is visually checked by the surgeon and cardiologist due to the absence of an intraoperative imaging technique able to evaluate its complex function. Noteworthy, most of the imaging techniques available to clinicians are established for the assessment of the left ventricle, with the ejection fraction being the most used parameter. However, this value is a measure of global systolic function which comes short in identifying regional myocardial impairment and the mechanical contraction. Therefore, new approaches are needed to deeply investigate the mechanics of both ventricles and correctly assess the cardiac mechanical performance. In this thesis, I studied the mechanical function of the left ventricle through different modalities of cardiac magnetic resonance and employed an innovative imaging technique for the assessment of the right ventricle mechanical function during open chest surgery

EVALUATION OF LEFT VENTRICULAR AND ATRIAL-APPENDAGE FUNCTION IN NORMAL AND ISCHEMIC MOUSE MODELS BY CARDIAC IMAGING TECHNIQUES: A PHARMACOLOGICAL VALIDATION

Despite progress in diagnosis and treatment lead to a significant reduction of the rate of death attributable to cardiovascular disease (CVD), many efforts must to be done to modify the pathological process and enhance protection. Thus the development of new technologies for diagnosis and novel therapeutic agents is fundamental for clinicians and researcher. In the last decade, murine model had become a useful tool to study CVDs mechanism and to test new pharmacological treatments. Noninvasive imaging technique, specific for laboratory animals, provide the opportunity to image longitudinally the same animal, investigating the follow-up of pathologies and assessing the effect of pharmacological treatments. Aims of this work are to set up an animal model of myocardial infarction (MI) and cardiac imaging (cardiac magnetic resonance imaging and echocardiography) of left ventricle (LV), left atrium (LA) and appendage (LAA) in healthy mice, and then evaluate the global and regional functional-structural changes and remodeling occurring on LV, LA and LAA after MI, with or without pharmacological treatment. The in vivo imaging data were supported by morphological, histological and gene expression analysis. Results from this study described the regional area changes occurring on LV after MI with a progressive loss of contractility also in remote non-infarcted tissue; the presence of only three pulmonary veins entering LA and the presence of the large LAA which, working together with LA, plays an important role in LV filling. After MI not only LV but also LA and LAA remodel in order to maintain, with their enlargement, LV stroke volume. The pharmacological treatment with valsartan, a selective inhibitor of AT1 receptor of Ang II, influenced LV remodeling by reducing LV enlargement, infarct size, ECM gene expression (in particular collagen VIII, fibulin-2 involved in fibrosis and hypertrophy), preserving LV SV without affecting LAA and LA increase in dimension