Left ventricular (LV) volume analysis in small animals has proven difficult because of the small size of the hearts and the rapid heart rate. Furthermore, there is a substantial contribution to the signal from both the blood as well as the muscle. Admittance - based measurement techniques has been proven effective in eliminating the muscular component and estimating the blood component accurately. The key factor that makes this measurement effective is the fact that the measurement is made in the complex plane, which measures both the magnitude as well as the phase of the complex phasor. This dissertation presents the design of a wireless telemetric device that measures impedance magnitude and phase measurements along with pressure from conscious, ambulatory rats. Using this impedance data along with other calibration data such as blood resistivity, stroke volume etc., volume is determined. / text

Not available / text

published_or_final_version / Community Medicine / Master / Master of Philosophy

Left ventricular flows in the human heart are very complex and in the presence of a diseased condition, such as unhealthy or prosthetic heart valves, the complexity of the flow is further increased. The intricacy of the heart geometry combined with the pulsatile character of the flow, the interaction of high-speed jets with the flexible walls, and the unsteady motion of the heart valve leaflets generate inherently complicated flow fields. It is therefore essential that we study and understand the complex cardiac energetics and physics of blood flow in both healthy and diseased hearts. Although artificial heart valves, mechanical and biological, have evolved to a level of universal acceptance, they have never reached a level of performance comparable to that of the natural valves of the heart. Many of the problems are directly related to the fluid mechanics. Considering that mechanical heart valves (MHV) are more commonly implanted because of their durability, it is imperative to better understand their hemodynamic behavior. Yet to date, no study has documented in depth the complex hemodynamic characteristics of left ventricular flows and assessed the intricate structures that are generated in the left ventricle (LV) due to vortex formation (roll-up of shear layers shed past the valve leaflets), turbulence characteristics, and energetics. The flow through pivoted leaflets of MHVs induces a combination of flow characteristics that are dependent on the specific valve design and orientation. The aim of the present study is to provide new insight into the spatio-temporal dynamics of the flow distal to a mitral MHV by employing a state-of-the-art, high resolution, flow diagnostic method, Time Resolved Digital Particle Image Velocimetry (TRDPIV) in a flexible, transparent LV documenting the evolution of eddies and turbulence during a complete period of the heart cycle. The broad impact of the proposed research extends beyond the hemodynamics of heart valve prosthesis. The research herein will enable the development of a tool for application in all cardiac energetic studies (unhealthy valves, tissue engineered valves, cardiac remodeling stages, and even congestive heart failure) and aid in better diagnosis of the efficiency and performance of the heart. The last component of the dissertation involved the translation of my dissertation research into an engineering educational tool for undergraduate engineering students. / Ph. D.

Left ventricular pumping performance may be described by intraventricular pressure and volume variables, usually presented as a pressure-volume plot. However, on-line monitoring of left ventricular pressure and volume with high temporal resolution requires the use of an invasive catheter technique such as, for example, the conductance catheter method. On the other hand, the very invasiveness and complexity of this approach makes it less suitable for clinical use. It is then not surprising that there has been long-felt need to make the conductance method less invasive and attempts have been made to adjust the method to clinical demands and routine in order to extract more information from pressure-volume interplay and possibly translate relevant data to their non-invasive estimates. In the present studies, a standard five segmental conductance catheter was used in animal (pig) experiments. Segmental conductances were compared to global conductance. Since the mid-ventricular segment was shown to reflect global volume, which was also shown on theoretical basis, it was concluded that a single segmental catheter most probably could be used to estimate global left ventricular volume. Subsequently, a thin and flexible single segmental conductance catheter was constructed and applied to an animal (pig) experimental model. Results were reproducible and very few arrythmias were detected. At the next stage, left ventricular isovolumic phases were investigated using the standard conductance catheter method, as well as echocardiographically derived tissue velocity doppler. Conductance was shown to decrease during isovolumic contraction, and an adjustment method was proposed in order to account for the subsequent decrease in pressure-volume loop area. In separate experiments, the left ventricular pressure wave form during left ventricular systole was examined, and an algorithm was proposed to discriminate between the changes in afterload, preload and contractility. Results showed clearly discernible patterns of the respective load and contractility alternation. Finally, the left ventricular continuous area was monitored continuously during the entire cardiac cycle as a measure of left ventricular volume dynamics in normal subjects and three patients with left ventricular abnormalities using echocardiographic automatic boundary detection. The left ventricular area thus obtained was plotted against its first derivative, to form a flow-volume estimates loop, in accordance with the flow-volume examinations used in respiratory physiology. Data obtained from the abnormal ventricles were presented as flow-volume estimates loops, exemplifying the possible use of the method. / QC 20100922

A proteomic procedure for analyzing mouse left ventricular collagen by mass spectrometry has been developed. The procedure involves a purification step that removes non-collagenous cellular components from the collagen extracellular matrix, a step that solubilizes the collagen in aqueous solvents before it is proteolytically digested for analysis with ESI-LCMS/MS. Collagen from healthy and lathrytic mice has been positively identified by applying the SEQUEST database search algorithm to spectra from the collagen prepared using this procedure. Analysis shows that the relative percentage of collagen peptides detected in lathrytic tissue is significantly greater than that of the healthy tissue. These preliminary results suggest that the percentage of cross-linked collagen is lower in the lathrytic tissue as indicated by the greater protein sequence coverage obtained for this tissue. This procedure lays the ground work for future experimentation that has the ability to allow for the identification and quantification of cross-linked peptides.

This study examines the α-adrenergic constrictor tone varies with intensity of exercise, the effects of coronary α1-adrenergic blockade on left ventricular contractile function and regional myocardial perfusion, and compares the effects of increasing coronary blood flow by removing α1-constrictor tone.

Understanding the mechanisms governing left ventricular function and dysfunction is critical to analyze cardiovascular disorders and gaining insights into possible therapies. Left ventricular function can be evaluated using Magnetic Resonance Imaging (MRI). Cardiac displacements and corresponding strains are then computed from the imaging data. In measuring and assessing the left ventricle’s motion, images are taken either in the short axis (top-down) or long axis (side) views. In this project, we will use DENSE MRI data, which measures the displacements of individual tissue voxels during the cardiac cycle. After extracting the myocardial tissue by segmenting the MR images, strains are computed by differentiating the displacement field in the radial direction (across the thickness of the heart wall), longitudinal direction (along the left ventricle long axis), and in the circumferential direction. Current approaches focus mainly on evaluating cardiac motion and strains during ventricular systole, when the ventricles contract and blood is pumped out of the heart ~\cite{srichai2009cardiovascular}. Our aim is to characterize strains during atrial systole, which corresponds to the late filling of the ventricles before the next contraction occurs. Understanding the deformation of the left ventricle during late filling is particularly important to evaluate the passive response of the myocardium, which is related to several cardiac diseases, such as heart failure with preserved ejection fraction and diabetic cardiomyopathy. During this study we will use preclinical data already acquired in healthy swine subjects. Our goal is to evaluate inter subject variability at peak atrial systole and how different segmentations (intra and inter observer variability) affect the computed strains.

In this study, lumped parameter cardiovascular modeling has been used to understand the influence of muscle properties on mechanical dyssynchrony (MD) as well as general muscle dynamics. Incorporating viscous influence into the model allowed for an expanded view when analyzing muscle parameter response to MD. A unique method of ventricle segmentation was introduced that allowed fast analysis of regional and global ventricular properties. This segmentation process produced a ventricle with four identical sections each consisting of separately tunable muscle properties in the form of minimum and maximum elastance, elastance waveform delay, and myocardial viscous friction, yet these regional sections remained globally dependent. Elastance waveform delay proved to be the most influential property on MD as measured by internal flow fraction (IFF), followed by regional elastance magnitude, and finally regional viscosity influence. Due to the unique segmentation of this model, two metrics for IFF were derived: (1) the "true" IFF (IFF-4seg) and (2) the IFF as would be measured by an ideal conductance catheter (IFF-CC). The results of IFF-CC versus IFF-4seg show that conductance catheters are not capable of measuring IFF during a side-to-side volume transfer within the stacked cylinder under measurement. Finally, unique energetic situations were observed with this model that point to likely myocardium remodeling situations.

There is a growing epidemic of chronic heart failure (CHF) in the developed world. The costs associated with providing care is profound and despite our best efforts, new, more effective treatments for CHF are needed; 50% of patients diagnosed with CHF are dead within 5 years. Current paradigms rely heavily on pharmacologic interventions, which merely help manage the disease. Surgical interventions may also be considered for late stage CHF patients such as heart transplant or left ventricular assist device (LVAD) but require burdensome and invasive surgical procedures. In addition they are costly, and require the need for life long immunosuppressive and anticoagulant therapies respectively. Despite our best intentions, the long-term prognosis for CHF patients remains poor. With over a decade of clinical investigation taken place, data from cell-based therapy trials remains inconsistent. While demonstrating safety, limited efficacy has been reported and to date, no stem cell therapy has been approved by the FDA. Despite these shortcomings important lessons have been learned that can be applied to future developments. Retrospective analysis of early cell-based clinical trial data has suggested that variations in isolated cell number, viability, and potency from donor to donor in autologous preparations yielded wide discrepancies in functional outcomes. In addition, sub culturing adult stem cells, even for short periods of time in 2D polystyrene environments void of complementary cell populations and extra cellular matrix protein interactions, may alter the therapeutic potential of a given cell. As a solution, allogeneic approaches where donor cell quality and potency can be assessed and optimized may help achieve functional benefits. Furthermore, co-dosing with multiple cell populations or developing 3D sub-culture environments that more closely mimic the in vivo milieu may ultimately yield more potent therapeutic cell populations. While these alterations may improve cell-based therapy outcomes, other solutions have been proposed such as tissue engineering. While the concept of tissue engineering is not new, advancements in biomaterials, bioreactor design and cell sources have greatly enhanced the reality of these preparations. Previously, one of the greatest limitations to tissue engineering is overcoming the cell requirements for developing and testing where millions if not billions of cells are required. Cell sourcing limitations appear to have been solved with the discovery and development of induced pluripotent stem cell (iPSC) derived cell populations. First reported in 2007, they have the ability to generate embryonic like pluripotent stem cells without the ethical concerns of embryonic stem cells. These iPSCs hold tremendous potential for drug toxicology / screening, personalized medicine and cell therapies. The body of work described in this dissertation looks at developing and testing a tissue engineered cardiac patch to treat heart failure. For which, an emphasis has been to provide 1) structural support for engrafted cells and 2) a rapidly inducible vascular supply once implanted in vivo. Biomaterials were sourced that facilitate infill by multiple cell populations in 3D culture and the establishment of extra cellular matrix deposits. Together, these patches enhanced cellular development in vitro and result in long term functional improvements in small animal models for CHF. Additional feasibility work was performed in large animal models to permit upscaling and development of surgical implantation techniques to demonstrate clinical applicability