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Cardiovascular disease (CVD) consistently ranks among the leading causes of death in the United States. The most common subtype of CVD, ischemic heart disease, is a frequent precursor of myocardial infarction and heart failure, most commonly affecting the left ventricle (LV). Today, echocardiography is regarded as the gold standard in screening, diagnosis, and monitoring of LV dysfunction. But while global assessment of LV function tends to be quantitative, cardiologists with specific expertise still perform many regional evaluations subjectively. However, a more objective and quantitative measure of regional function – myocardial strain – has been developed and widely studied using 2D echocardiography. With recent developments in real-time 3D echocardiography (RT3DE), it has become possible to measure strain in its native 3D orientation as well. Our laboratory’s earlier work introduced the Optical Flow (OF) method of strain analysis, which was validated on simulated echocardiograms as well as through animal studies. The principal goal of this thesis is to translate this OF-based method of strain estimation from the research setting to the patient’s bedside. We have performed a series of studies to evaluate the feasibility, accuracy, and reproducibility of OF-based myocardial strain estimation in a routine clinical setting. The first investigation focused on the optimization of RT3DE acquisition and the OF processing pipeline for use in human subjects. Subsequently, we evaluated the capacity of this technique to distinguish abnormal strain patterns in patients with CVD and varying degrees of LV dysfunction. Our analysis revealed that segmental strain measures obtained by OF may have better sensitivity and specificity than the more commonly used global LV strains. Our third validation study examined the reproducibility of these strain measures in both healthy and diseased populations. We established that OF-based strain measures demonstrate repeatability comparable to that achieved by the latest commercial software commonly used in clinical research to estimate 2D or 3D strain. These studies were driven in large part by the absence of a ground truth or accepted gold standard of 3D strain measurements in the human LV. However, cardiac magnetic resonance imaging has had considerable success in measuring some forms of strain in the human LV. We therefore began to develop an image-processing pipeline to derive strain estimates from a new pulse sequence called 3D-DENSE. We further sought to improve the OF pipeline by automating the process of tracking the LV border. To this end, we developed a level-set based technique which tracks the LV endocardium. Our evaluation of its performance on RT3DE data confirmed that this method performs within the limits of inter-observer variability. Overall, our pilot studies of OF-based strain estimation demonstrate that the technique possesses several promising features for improving cardiologists’ ability to quantify and interpret the complex three-dimensional deformations of the human LV.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Made available in DSpace on 2014-06-11T19:23:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2007-02-27Bitstream added on 2014-06-13T18:09:26Z : No. of bitstreams: 1 leopoldo_apl_me_botfm.pdf: 868546 bytes, checksum: ae589c359f7d763a9434d78a77379f51 (MD5) / A obesidade é caracterizada pelo acúmulo excessivo de gordura corporal, representando um problema de abrangência mundial que afeta principalmente países industrializados. As comorbidades acarretadas pela obesidade resultam em conseqüências econômicas para a saúde pública e estão associadas com prejuízo da qualidade de vida e aumento da mortalidade. Pesquisas clínicas mostram que o excesso de gordura acarreta diversas anormalidades cardíacas, as quais se relacionam com a duração e intensidade da obesidade. Modelos experimentais, como a obesidade induzida por dieta hipercalórica, têm sido utilizados para o estudo das alterações moleculares, bioquímicas, morfológicas e funcionais acarretadas pelo acúmulo de tecido adiposo. Em razão da carência de estudos relacionando obesidade por dieta hipercalórica e cálcio intracelular miocárdico, o objetivo deste estudo foi analisar a expressão gênica das proteínas do sarcolema, canal L e trocador Na+/Ca2+ (NCX), e do retículo sarcoplasmático, ATPase de cálcio (Serca 2a), receptor rianodina (RyR), fosfolambam (PLB) e calsequestrina (CSQ2), envolvidas na regulação do cálcio intracelular miocárdico de ratos obesos. Ratos Wistar machos, com 30 dias, foram randomizados em dois grupos: controle (C; n=13) e obeso (Ob; n=13). O grupo C recebeu ração Labina (3,3 Kcal/g) e o Ob um ciclo de cinco dietas hipercalóricas ( 4,5 kcal/g) durante 15 semanas. Foram analisados: peso corporal final (PCF), porcentagem de gordura da carcaça (% GC), pressão arterial sistólica final (PA), peso dos ventrículos esquerdo (VE) e direito (VD) e as relações VE/PCF e VD/PCF. O perfil glicêmico foi estimado pelo teste de tolerância à glicose (GTT) e os níveis plasmáticos de insulina e leptina avaliados por ELISA. A expressão gênica das proteínas envolvidas no trânsito de cálcio foi analisada por RT-PCR. Os dados foram expressos... / The obesity is characterized by the extreme accumulation of corporal fat, representing a problem of world-wide embracing that mainly affects industrialized countries. The comorbidities caused by the obesity result in economic consequences for the public health and they are associated with damage of the life quality and increase of mortality. Clinical research shows that the fat excess causes diverse heart abnormalities, which relates with the duration and intensity of the obesity. Experimental models, as the induced obesity by high fat diet, have been used for the study of the molecular, biochemical, morphologic and functional alterations caused by the accumulation of fat tissue. In despite of the lack of studies relating to obesity by high fat diet and myocardium intracellular calcium, the objective of this study was to analyze the expression gene of sarcolemal proteins, L type channel and exchanger Na+/Ca2+ (NCX), and of the sarcoplasmic reticulum, ATPase of calcium (Serca2a), ryanodine receptor (RyR), phospholamban (PLB) and calsequestrin (CSQ2), involved in the regulation of myocardium intracellular calcium of obese rats. Male Wistar rats, with 30 days, were randomly in two groups: control (C; n=13) and obese (Ob; n=13). Group C received a control low-fat diet Labina (3,3 Kcal/g) and the Ob cycles from five high fat diets (4,5 kcal/g) during 15 weeks. Final corporal weight (FBW), percentage of fat of the carcass (%CF), final systolic blood pressure (SBP), weight of the left ventricles (LV) and right (RV) and the ratio LV/FBW and RV/FBW were analyzed. The profile glucose was esteemed by the oral glucose tolerance test (GTT) and the insulin and leptin plasma levels evaluated by ELISA. The expression gene of Ca2+ cycling proteins was analyzed by semi-quantitative RT-PCR. The data were expressed in means l SD... (Complete abstract click electronic access below)

Indiana University-Purdue University Indianapolis (IUPUI) / Dishevelled-associated activator of morphogenesis 1 (Daam1), a member of the formin protein family, has been implicated in the non-canonical Wnt mediated Planar Cell Polarity (PCP) signaling pathway. Although the studies in Drosophila Daam1 and Xenopus Daam1 generated inconsistent conclusions regarding the function of Daam1, the biological function of mammalian Daam1 was not evaluated. In this study, we used a mouse promoter trap technology to create Daam1 deficient mice to analyze the role of Daam1 in embryonic development and organogenesis. Daam1 is highly expressed in the developing heart. The majority of Daam1 mutant mice died between embryonic day 14.5 and birth, exhibiting a variety of heart defects, which include ventricular noncompaction, ventricular septal defects, and double outlet right ventricle. About 10% mutant mice survive to adulthood, and these survivors do not show significantly compromised heart function based on echocardiographic analyses. However, all of these mutant survivors have ventricular noncompaction with a range of severities. A conditional rescue experiment using a cardiac specific Cre mouse line, Nkx2-5Cre, confirmed that the cardiac defects are the primary cause of death in Daam1 mutants. Both in vivo and ex vivo analyses revealed that Daam1 is essential for regulating non-sarcomeric filamentous actin assembly in cardiomyocytes, which likely contributes to cardiac morphogenesis and ventricular wall maturation. Biochemical studies further suggested that Daam1 is not a key signaling component in regulating the activation of small GTPases, such as RhoA, Rac1 and Cdc42. In conclusion, our studies demonstrated that Daam1 is essential for cardiac morphogenesis likely through its regulation of cytoskeletal architecture in the developing cardiomyocytes. / indefinitely

Indiana University-Purdue University Indianapolis (IUPUI) / Congenital heart defects occur in approximately one percent of births every year, which makes it the most frequently occurring congenital defect in patients. The aim of this project was to use two mutant neural crest (NC) mouse models to study the mechanisms underlying congenital heart failure in utero. The first mouse model was a Pax3 systemic knockout, which was lethal by mouse gestational day 14, and had appreciably reduced numbers of migratory NC cells. The second mouse model was a Wnt1Cre-mediated NC genetic cell ablation model, which was surprisingly viable and survived to birth, despite an apparent lack of migratory NC cells. The resultant data indicated that both mouse models had similar heart structural defects including persistent truncus arteriosus, which was due to fewer or no migratory cardiac NC cells. However, in utero heart function was appreciably perturbed in Pax3 mutants when compared to that of the ablated mutant model. The loss of embryonic cardiac function in Pax3 mutants was directly attributed to a substantial decrease in the activity of the beta-adrenergic pathway. This was due to a lack of proper specification of trunk NC cells, leading to diminished levels of circulating catecholamine levels in the embryo. To definitively confirm this conclusion, poor cardiac function was successfully restored by pharmacological stimulation of the beta-adrenergic pathway via administration of isoproterenol and forskolin to pregnant dams, which led to embryonic survival of Pax3 mutants to birth. By comparison of these two mutant mouse models, perturbation in the beta-adrenergic pathway was identified as the underlying mechanism responsible for in utero heart failure and lethality in Pax3 mutant embryos. The results of this study are expected to be significant in developing future therapeutic targets for congenital heart failure in prenatal and newborn patients.

Single ventricle heart defects are a rare but serious form of congenital heart disease, which affect approximately 2000 children born in the United States each year. Staged surgical palliation, culminating with the “Fontan Procedure,” is typically required to achieve adequate supply of blood to both the pulmonary and systemic circulations while avoiding chronic ventricular volume overload. This surgery reroutes the systemic veins to the pulmonary arteries, forming a total cavopulmonary connection (TCPC), to completely bypass the right side of the heart and restore a series configuration to the cardiovascular circuits. Despite improved survival through this operative course in first weeks and years of life, Fontan patients are subjected gradual attrition and decreased life expectancy through a multitude of chronic complications. It is suspected that the adverse hemodynamics of this surgically altered physiology, including those specific to the surgical TCPC, play a role in determining patient outcome. However, the small and heterogeneous patient population has hindered decisive progress and there is still not a good understanding of the optimal care strategies on a patient-by-patient basis. In recent decades, advances in medical imaging and image-based computational fluid dynamics (CFD) have redefined the realm of possibility for studying complex biomedical phenomena. Combined, these methods provide the means to create and evaluate patient-specific models of a wide range of cardiovascular structures, including the TCPC, with high fidelity. Results from these models can then be used for a wide array of different analyses, such as identifying regions of flow separation or stagnation, calculating hemodynamic power loss, or quantifying local flow distribution patterns. Through significant effort from numerous past investigators, a robust set of validated computational and image processing tools has been assembled, along with the largest library of cardiac magnetic resonance (CMR) data of TCPC anatomy and flow. These tools are leveraged in this thesis to characterize the functional implications of TCPC power loss at an unprecedented scale: we report the largest CFD analysis of patient-specific TCPC hemodynamics to date with particular focus on identifying functional correlates. Combining these data with imaging-based analysis of ventricle function, we directly compare the CFD-derived hemodynamics to the performance of the single ventricle for the first time. Motivated by the physiologic significance of these findings, the same patient-specific CFD framework is used for the translational application of prospective surgery planning for hemodynamic optimization, including the first implementation of a novel TCPC connection design hypothesized to uniquely streamline the energetic performance. We conclude with a first look at the longitudinal evolution of patient functional status to begin understanding how factors such as TCPC hemodynamics contribute to poor long-term performance in these patients.

Single ventricle heart defects, where systemic and pulmonary venous returns mix in the single functional ventricle, represent the most complex form of congenital heart defect, affecting 2 babies per 1000 live births. Surgical repairs, termed "Fontan Repairs," reroute the systemic venous return directly to the pulmonary arteries, thus preventing venous return mixing and restoring normal oxygenation saturation levels. Unfortunately, these repairs are only palliative and Fontan patients are subjected to a multitude of chronic complications. It has long been suspected that hemodynamics play a role in determining patient outcome. However, the number of anatomical and functional variables that come into play and the inability to conduct large scale clinical evaluations, due to too small a patient population, has hindered decisive progress and there is still not a good understanding of the optimal care strategies on a patient-by-patient basis. Over the past decades, image-guided computational fluid dynamics (CFD) has arisen as an attractive option to accurately model such complex biomedical phenomena, providing a high degree of freedom regarding the geometry and flow conditions to be simulated, and carrying the potential to be automated for large sample size studies. Despite these theoretical advantages, few CFD studies have been able to account for the complexity of patient-specific anatomies and in vivo pulsatile flows. In this thesis, we develop an unstructured Cartesian immersed-boundary flow solver allowing for high resolution, time-accurate simulations in arbitrarily complex geometries, at low computational costs. Combining the proposed and validated CFD solver with an interactive virtual-surgery environment, we present an image-based surgical planning framework that: a) allows for in depth analysis of the pre-operative in vivo hemodynamics; b) enables surgeons to determine the optimum surgical scenario prior to the operation. This framework is first applied to retrospectively investigate the in vivo pulsatile hemodynamics of different Fontan repair techniques, and quantitatively compare their efficiency. We then report the prospective surgical planning investigations conducted for six failing Fontan patients with an interrupted inferior vena cava and azygous continuation. In addition to a direct benefit to the patients under consideration, the knowledge derived from these surgical planning studies will also have a larger impact for the clinical management of Fontan patients as they shed light onto the impact of caval offset, vessel flaring and other design parameters upon the Fontan hemodynamics depending on the underlying patient anatomy. These results provide useful surgical guidelines for each anatomical template, which could benefit the global surgical community, including centers that do not have access to patient-specific surgical planning interfaces.

Acute Coronary Syndrome (ACS) is common and associated with high mortality. Effective treatments are available but require prompt administration. Studies have consistently demonstrated that delays to treatment are common, with patient decision time accounting for most delay. Interventions aimed at reducing delay have had little success. Evidence suggests that psychological factors, in particular illness representations (Leventhal’s Commonsense Model of Self-Regulation (CS-SRM)) might be important in relation to patient decision time. This thesis describes a two-stage investigation, undertaken within NHS 24, exploring the content and timing of people’s initial presentations with possible symptoms of ACS. The first stage comprised a CS-SRM-guided content analysis of peoples’ initial symptom presentations. The second stage utilised the Illness Perception Questionnaire-revised (IPQ-R) to explore how illness representations relate to patient decision time. Results show that the components of illness representations accounted for 95% of participants’ initial presentations. The components most related to behaviour and outcome were volunteered least (cause, consequences, cure/control and coherence). Decision time for most participants (89%) was out-with the ideal and appraisal time accounted for most of the delay. Appraisal delay was shorter for those with fewer symptoms and high emotion. Illness delay was longer where the person making the call reported high treatment control. Interventions may need to raise awareness of the range of possible presentations and of the consequences associated with delay. Interventions should also provide guidance as to an appropriate time-limit for self-care. Individuals may benefit from being informed about how to respond to strong emotional responses. Interventions aimed at bystanders may need to differ from those for patients. People at high risk of ACS should be informed about how and when to access healthcare out-of-hours.