D.Litt. et Phil. / This research investigated the effectiveness of the treatment programme used by the South African Recurrent Coronary Prevention Project (SARCPP) in reducing the risk of not only recurrent heart disease, but also of original occurrence of heart disease. Heart disease can often be attributed to lifestyle factors such as obesity, high fat content diets and smoking (Friedman & Ulmer, 1995 and Richards & Baker, 1988). Another lifestyle risk factor of heart disease is Type A behaviour, as first discovered by Rosenman and Friedman (1959). Type A behaviour is made up of various components, such as hostility, time urgency and insecurity. The SARCPP has effectively reduced Type A behaviour in past studies (Venter, 1993; Viljoen, 1993; MacLennan, 1994 and Webster, 1994) and it has been found that reducing Type A behaviour through this programme increases high density lipoproteins and decreases total triglycerides, thus decreasing physiological risk factors of heart disease (Wolff, Thoresen, Viljoen, & Venter, 1994). The SARCPP thus far had only been used with Type A persons who had already suffered a form of heart disease, such as myocardial infarction and angina pectoris (here called "unhealthy" Type As). Other interventions have been used to decrease Type A behaviour in subjects who had not yet suffered heart disease (or "healthy" Type As). A leading researcher in this field is Ethel Roskies (1979-1990). Due to ineffective measurement and ineffective treatment programmes, her attempts were not successful, though. This research study applied the treatment used in the SARCPP to both "healthy" and "unhealthy" Type As and it was found that it was as successful in reducing Type A behaviour in both the "healthy" subjects as in the "unhealthy" subjects. Not only was global Type A behaviour as measured by the Videotaped Structured Interview decreased in the treatment groups, but so were the components of Hostility, Time Urgency and Insecurity (although Insecurity was not decreased in the "unhealthy" subjects). The tendency by the subjects to repress angry feelings was reduced in both "unhealthy" and "healthy" subjects, as was cynical hostility in the "healthy" subjects. It was found that the "unhealthy" subjects had significantly more State and Trait anxiety before the treatment took place than the "healthy" subjects and that the treatment reduced that anxiety in the "unhealthy" subjects significantly. Depression was decreased in both "healthy" and "unhealthy" subjects. Thus, the treatment programme of the SARCPP was effective in reducing coronary-prone behavioural factors and can be used as both prevention in recurrence and prevention in original occurrence of heart disease.

In developing countries, acute respiratory infections (ARIs) are responsible for two million deaths per year. Most victims are children who are less than 5 years old. Pneumonia kills 5000 children per day. The statistics for cardiovascular diseases (CVDs) are even more alarming. According to a 2009 report from the World Health Organization (WHO), CVDs kill 17 million people per year. In many resource-poor parts of the world such as India and China, many people are unable to access cardiologists, pulmonologists, and other specialists. Hence, low skilled health professionals are responsible for screening people for ARIs and CVDs in these areas. For example, in the rural areas of the Philippines, there is only one doctor for every 10,000 people. By contrast, the United States has one doctor for every 500 Americans. Due to advances in technology, it is now possible to use a smartphone for audio recording, signal processing, and machine learning. In my thesis, I have developed an Android application named Smart Auscultation. Auscultation is a process in which physicians listen to heart and lung sounds to diagnose disorders. Cardiologists spend years mastering this skill. The Smart Auscultation application is capable of recording and classifying heart sounds, and can be used by public or clinical health workers. This application can detect abnormal heart sounds with up to 92-98% accuracy. In addition, the application can record, but not yet classify, lung sounds. This application will be able to help save thousands of lives by allowing anyone to identify abnormal heart and lung sounds.

Heart Failure is a leading cause of death and disability worldwide. The identification of risk factors of heart failure in healthy individuals is key to improve disease prevention and reduce mortality. Metals exposures are recently established cardiovascular disease risk factors, but their association with heart failure remains understudied and prospective studies across diverse populations are needed. Metals are widespread in the environment, some of the sources of exposure include drinking water, air, and soil contamination. Some population groups, particularly American Indian, Hispanic/Latino, and Black communities in the United States are exposed to higher levels of environmental metals as a result of sociodemographic and structural factors including structural racism. These population groups suffer a higher burden of heart failure compared to White populations. Importantly, the burden of heart failure in American Indian communities in the United States, a population group with high rates of diabetes, hypertension, and other cardiovascular disease risk factors, is underreported, and key risk factors of heart failure in these population groups remain understudied. This dissertation characterized relevant risk factors of heart failure in American Indian participants from the Strong Heart Study. Towards the goal of identifying novel preventable cardiovascular disease risk factors, it comprehensively assessed the sources of exposure and biomarkers for multiple non-essential and essential metals with a focus on characterizing drivers of disparities in drinking water metal concentrations. Then, it evaluated the role of exposure to multiple metals (individually and as a mixture) on the risk of heart failure and overall cardiovascular disease and all-cause mortality, leveraging three geographically and racially and ethnically diverse population-based cohorts: the Multi-Ethnic Study of Atherosclerosis (MESA), the Strong Heart Study (SHS), and the Hortega cohort. Last, it identified and evaluated new opportunities for the mitigation of metal toxicity through nutritional interventions. Chapter 1 provides background information about heart failure epidemiology and pathophysiology, the role of environmental metals on cardiovascular disease, and introduces the dissertation framework necessary to contextualize the work included in this dissertation. Chapter 2 estimated the incidence of heart failure in the SHS, a large epidemiological cohort of American Indian adults from Arizona, Oklahoma, North Dakota, and South Dakota, followed from 1989-1991 through 2019. A parsimonious heart failure-risk prediction equation that accounts for relevant cardiovascular risk factors affecting American Indian communities was developed. The incidence rate of heart failure was 9.5 per 1,000 person-years, with higher rates across participants with diabetes, hypertension, and albuminuria. Significant predictors for heart failure risk at 5 and 10 years included age, smoking, albuminuria, and previous myocardial infarction. Diabetes diagnosis and higher levels of HbA1c were significant predictors of risk at 10 and 28 years. Models achieved a high discrimination performance (C-index (95%CI): 0.81 (0.76, 0.84) at 5 years, 0.78 (0.75, 0.81) at 10 years, and 0.77 (0.74, 0.78) up to 28 years), and some associations varied across HF subtypes. Chapter 3 developed a comprehensive overview of the main sources and routes of exposure, biotransformation, and biomarkers of exposure and internal dose for 12 metals/metalloids, including 8 non-essential elements (arsenic, barium, cadmium, lead, mercury, nickel, tin, uranium) and 4 essential elements (manganese, molybdenum, selenium, and zinc), providing a set of recommendations for the use and interpretation of metal biomarkers in epidemiological studies. Chapter 4 conducted the first nationwide geospatial analysis identifying racial/ethnic inequalities in arsenic and uranium concentrations in public drinking water across the conterminous United States using geospatial models. The association between county-level racial/ethnic composition and public water arsenic and uranium concentrations (2000-2011)was assessed. Higher proportions of Hispanic/Latino and American Indian/Alaskan Native residents were associated with 6% (95% CI: 4-8%), and 7% (3-11%) higher levels of arsenic, and 17% (13-22%), and 2% (-4-8%), higher levels of uranium, respectively, in public drinking water, after accounting for relevant social and geological indicators. Higher county-level proportions of non-Hispanic Black residents were associated with higher arsenic and uranium in the Southwest, where concentrations of these contaminants are high. These findings identified the key role of structural racism as driver of drinking water metal concentrations inequalities. Chapter 5 evaluated the prospective association between urinary metal levels, a established biomarker of internal dose, and incident heart failure across three geographically and ethnically/racially diverse cohorts: MESA and SHS in the United States, and the Hortega Study in Spain. These findings consistently identified significant associations across cohorts for cadmium (pooled hazard ratio: 1.15 (95% CI: 1.07, 1.24), tungsten (1.07 (1.02, 1.12)), copper (1.31 (1.18, 1.45)), molybdenum (1.13 (1.05, 1.22)), and zinc (1.22 (1.14, 1.32))). Higher levels of urinary metals analyzed as a mixture were significantly associated with increased incident heart failure risk in MESA and SHS, and non-significantly increased in the Hortega Study, which has a smaller number of events. Chapter 6 assessed the prospective association of urinary metals with incident cardiovascular disease and all-cause mortality in MESA, including a total of 6,599 participants at baseline (2000-2001), followed through 2019. Significant associations between higher levels of urinary cadmium, tungsten, uranium, cobalt, copper, and zinc, and higher risk of CVD and all-cause mortality were identified. A positive linear dose-response was identified for cadmium and copper with both endpoints. The adjusted HRs (95%CI) for an interquartile range (IQR) increase in the mixture of these six urinary metals and the correspondent 10-year survival probability difference (95% CI) were 1.29 (1.11, 1.56), and -1.1% (-2.0, -0.05) for incident CVD and 1.66 (1.47, 1.91), and -2.0% (-2.6, -1.5) for all-cause mortality. Chapter 7 investigated the effects of a nutritional intervention with folic acid (FA) and B12 supplementation on arsenic methylation in children exposed to high levels of drinking water arsenic in Bangladesh. The randomized controlled trial included a total of 240 children 8-11 years old. Compared to placebo, the supplementation group experienced a significant increase in the concentration of blood DMA, a non-toxic arsenic metabolite, by 14.0% (95%CI: 5.0, 25.0) and blood secondary methylation index (DMAs/MMAs) by 0.19 (95%CI: 0.09, 0.35). Similarly, there was a 1.62% (95%CI: 0.43, 2.83) significantly higher urinary %DMAs and -1.10% (CI: -1.73, -0.48) significantly lower urinary %MMAs compared to placebo group after 1 week. These results confirmed that FA+B12 supplementation increases arsenic methylation in children as reflected by decreased MMAs and increased DMAs in blood and urine. Altogether, the findings presented in this dissertation consistently identify the role of urinary metals as robust risk factors of heart failure, overall cardiovascular disease and all-cause mortality across diverse populations. With consistent findings across multiple assessments of the dose response relationship and mixture approaches. Additionally, this dissertation work contributes to address disparities in environmental exposures and heart failure burden, respectively, by characterizing the impact of structural racism drinking water metal exposures disparities and identifying relevant risk factors of heart failure in American Indian populations who are historically underrepresented in epidemiological cohorts. Last, this dissertation identifies the role of folic acid and B12 supplementation to reduce arsenic toxicity in children. These findings have direct clinical and policy implications, as they can inform the development of novel clinical guidelines to incorporate environmental factors in clinical risk prediction, and they can inform drinking water regulation and infrastructure efforts to support at risk communities and inform population-level nutritional recommendations and policies.

Širdies ir kraujagyslių ligos Lietuvoje kaip ir visame pasaulyje yra dažniausia mirtingumo priežastis. Pasiekti geresnių sveikatos rodiklių galima įtraukiant kuo daugiau gyventojų į sveiką gyvenseną skatinančias programas, tačiau svarbi visuma - programas reikalinga ir tinkamai valdyti. Darbo tikslas - įvertinti širdies ir kraujagyslių ligų prevencijos programos vykdymo efektyvumą Šiaulių mieste. Darbo uždaviniai: Išnagrinėti Asmenų, priskirtų širdies ir kraujagyslių ligų didelės rizikos grupei, atrankos ir prevencijos priemonių finansavimo programos reikalingumą, Lietuvos teisės aktus, reglamentuojančius programos įgyvendinimą. Išanalizuoti sergamumo ir mirtingumo nuo širdies ir kraujagyslių ligų duomenis ir statistikos rezultatus bei įvertinti programos įgyvendinimo situaciją Lietuvoje ir Šiauliuose. Įvertinti širdies ir kraujagyslių programos efektyvumą jos vartotojų ir vykdytojų požiūriu Šiaulių mieste ir pateikti programai pasiūlymus. Tyrimo objektas: Asmenų, priskirtų širdies ir kraujagyslių ligų didelės rizikos grupei, atrankos ir prevencijos priemonių finansavimo programa. Tyrimo dalykas: Asmenų, priskirtų širdies ir kraujagyslių ligų didelės rizikos grupei, atrankos ir prevencijos priemonių finansavimo programos efektyvumas, įgyvendinimas bei problemos. Darbo metodai: aprašomasis, palyginamosios analizės, istorinis, ir 3 sociologiniai tyrimai: kokybinis gydytojų ir pacientų nuomonės tyrimas ir kokybinis tyrimas – pusiau struktūruotas ekspertų interviu. Išvados:... [toliau žr. visą tekstą] / Heart and vascular diseases are the most frequent cause of mortality in Lithuania as well as in the whole world. It is possible to achieve better health rates involving as many people into programs encouraging and stimulating healthy lifestyle as possible, however the totality is also important – it is also necessary to manage appropriately the programs. Objective of the paper - to assess the efficiency of performance of the prevention program of heart and vascular diseases in Šiauliai City. Tasks of the paper: To consider the necessity of the program of financing of the measures of selection and prevention of people attributed to the group of high risk of heart and vascular diseases, as well as to analyse Lithuanian law acts regulating implementation of the program. To analyse data and statistical results on morbidity and mortality caused by cardiovascular diseases as well as to assess the situation of the program implementation in Lithuania and Šiauliai. To assess the efficiency of the program of cardiovascular diseases from the point of view of the users and implementers thereof as well as to give suggestions and advises to the program. Object of the research: the program of financing of selection and prevention measures of people attributed to the group of high risk of cardiovascular diseases. Subject of the research: the efficiency, implementation and problems of the program of financing of the selection and prevention measures of people attributed to the group... [to full text]

Les patients décrits initialement par J. Noonan se ressemblent et ont une cardiopathie congénitale :soit une sténose valvulaire pulmonaire (SVP), soit une persistance du canal artériel. Avant la découverte du premier gène responsable de ce qui est devenu le syndrome de Noonan, cinq études de cohortes décrivant ces patients ont répertorié la prévalence de SVP mais le spectre des cardiopathies semble large, n’a pas été décrit de manière exhautive et aucune hypothèse n’est émise ou ne fait de lien entre ces différentes manifestations cardiaques et une compréhension intégrée du développement embryonnaire. Le gène PTPN11 est le premier gène identifié chez 40% de ces patients. Une corrélation existe entre la présence d’une mutation et la survenue de SVP de même qu’entre l’absence de mutation et la présence d’une cardiomyopathie hypertrophique. Six études de cohortes ont repris la description des mutations identifiées au sein du gène PTPN11 et les phénotypes associés, mais les cardiopathies n’ont pas été systématiquement ou spécifiquement analysées (tant au sein des groupes de patients porteurs de mutation que de ceux sans mutation). Le syndrome LEOPARD est allélique du syndrome de Noonan depuis que des mutations spécifiques au sein des exons 7,12 et 13 du gène PTPN11 ont été identifiées chez 95% des patients. <p><p>Afin d’appréhender les implications possibles du gène PTPN11 dans la survenue des cardiopathies chez les patients porteurs de ces deux syndromes, nous avons conduit une étude chez 272 patients au syndrome de Noonan et une étude chez 19 patients porteurs du syndrome LEOPARD. Parmi la cohorte de patients atteints du syndrome de Noonan, 104 ont été diagnostiqués porteurs d’une mutation du gène (38%). Une prévalence de survenue de cardiopathies affectant les structures droites du cœur se dégage chez les patients identifiés porteurs d’une mutation avec une différence significative pour la SVP, une tendance est relevée pour le canal atrio-ventriculaire et la communication inter-auriculaire de type Ostium Secundum. L’absence de mutation est corrélée avec la survenue de cardiomyopathie hypertrophique et de cardiopathies du cœur gauche. Parmi les patients atteints du syndrome LEOPARD, il n’existe pas de différence statistiquement significative pour les patients porteurs d’une mutation ou non et/ou pour une cardiopathie particulière. <p><p>Toutes les mutations identifiées du gène PTPN11 sont des mutations ‘faux-sens’. Ce gène appartient à la famille des gènes codant pour une protéine tyrosyl phosphatase, SHP-2, ne possédant pas de récepteur trans-membranaire. Cette phosphatase est impliquée dans la voie de signalisation cellulaire des MAP (‘Mitogen-activated protein’) kinases dont l’expression est ubiquitaire et inclut le coeur. Depuis nos travaux, le concept de syndrome « neuro-cardio-facio-cutané » est établi puisque, à ce jour, 9 gènes (SOS1, RAF1, BRAF, KRAS, NRAS, HRAS, NF1, SPRED1 et SHOC2), tous impliqués dans la voie de signalisation RAS (voie des MAP kinases) sont identifiés. Un spectre phénotypique existe avec des signes communs mais aussi distinctifs chez les patients présentant le syndrome de Noonan, le syndrome LEOPARD, le syndrome de Costello, le syndrome Cardio-Facio-Cutané (CFC), le syndrome « Noonan-NF1 », le syndrome de Legius et le syndrome « Noonan/Multiple Giant Cell Lesion ». Nous rapportons enfin l’observation d’une patiente atteinte du syndrome CFC et porteuse d’une mutation (p.R257Q) au sein du gène BRAF ayant développé une cardiomyopathie hypertrophique. <p><p>Ces travaux de cohortes de patients au phénotype du syndrome de Noonan, du syndrome LEOPARD et cette dernière description d’une patiente au syndrome CFC ont permis de participer à la découverte de l’implication d’une voie de signalisation cellulaire dont l’origine génétique est maintenant démontrée. Les résultats de nos travaux réalisés depuis 2002 auront permis, avec les équipes travaillant sur le même sujet, d’orienter les investigations et les nouveaux projets de recherche qui étudient spécifiquement le rôle du gène PTPN11 dans l’embryologie du cœur. Les études des orthologues (zebrafish, murin et Drosophila) porteurs à l’état hétérozygote d’une mutation du gène PTPN11 permettent d’intégrer les anomalies phénotypiques et cardiaques observées. Ces études permettent de postuler les effets cellulaires produits par les mutations chez les patients atteints du syndrome de Noonan et chez les patients atteints du syndrome LEOPARD engendrant in vitro une activation de la phosphatase (effet « gain de fonction ») pour les premiers ou une réduction de l’activité phosphatase (« dominant négatif ») mais engendrant un effet gain de fonction in vivo. Nous discutons les connaissances acquises, les compréhensions obtenues et intégrées et traçons enfin les perspectives offertes par ces travaux.<p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Les maladies cardiovasculaires et en particulier les maladies coronariennes représentent la principale cause de mortalité mondiale avec 17,9 millions de décès en 2012. L’IRM cardiaque est un outil particulièrement intéressant pour la compréhension et l’évaluation des cardiopathies, notamment ischémiques. Son apport diagnostique est souvent majeur et elle apporte des informations non accessibles par d’autres modalités d’imagerie. Les travaux menés pendant cette thèse portent plus particulièrement sur l’examen dit de perfusion myocardique qui consiste à étudier la distribution d’un agent de contraste au sein du muscle cardiaque lors de son premier passage. En pratique clinique cet examen est souvent limité à la seule analyse visuelle du clinicien qui recherche un hyposignal lui permettant d’identifier l’artère coupable et d’en déduire le territoire impacté. Cependant, cette technique est relative et ne permet pas de quantifier le flux sanguin myocardique. Au cours de ces dernières années, un nombre croissant de techniques sont apparues pour permettre cette quantification et ce à toutes les étapes de traitement, depuis l’acquisition jusqu’à la mesure elle-même. Nous avons dans un premier temps établi un pipeline de traitement afin de combiner ces approches et de les évaluer à l’aide d’un fantôme numérique et à partir de données cliniques. Nous avons pu démontrer que l’approche Bayésienne permettait de quantifier la perfusion cardiaque et sa supériorité à évaluer le délai d’arrivé du bolus d’indicateur par rapport au modèle de Fermi. De plus l’approche Bayésienne apporte en supplément des informations intéressantes telles que la fonction de densité de probabilité de la mesure et l’incertitude sur la fonction résidu qui permettent de connaitre la fiabilité de la mesure effectuée notamment en observant la répartition de la fonction de densité de probabilité de la mesure. Enfin, nous avons proposé un algorithme de segmentation des lésions myocardiques, exploitant les dimensions spatiotemporelles des données de perfusion. Cette technique permet une segmentation objective et précise de la région hypoperfusée permettant une mesure du flux sanguin myocardique sur une zone de tissu dont le comportement est homogène et dont la mesure du signal moyen permet une augmentation du rapport contraste à bruit. Sur la cohorte de 30 patients, la variabilité des mesures du flux sanguin myocardique effectuées sur les voxels détectés par cette technique était significativement inférieure à celle des mesures effectuées sur les voxels des zones définies manuellement (différence moyenne=0.14, 95% CI [0.07, 0.2]) et de celles effectuées sur les voxels des zones définies à partir de la méthode bullseye (différence moyenne =0.25, 95% CI [0.17, 0.36]) / Cardiovascular diseases and in particular coronary heart disease are the main cause of death worldwide with 17.9 million deaths in 2012. Cardiac MRI is a particularly interesting tool for understanding and evaluating heart disease, including ischemic heart disease. Its diagnostic contribution is often major and it provides information that is not accessible by other imaging modalities. The work carried out during this thesis focuses more specifically on the so-called myocardium perfusion test, which consists in studying the distribution of a contrast agent within the heart muscle during its first passage. In clinical practice, this examination is often limited to the clinician's visual analysis, allowing him to identify the culprit artery and deduce the impacted territory. However, this technique is relative and does not quantify myocardial blood flow. In recent years, an increasing number of techniques have emerged to enable this quantification at all stages of processing, from acquisition to the measurement itself. We first established a treatment pipeline to combine these approaches and evaluate them using a digital phantom and clinical data. We demonstrated that the Bayesian approach is able to quantify myocardium perfusion and its superiority in evaluating the arrival time of the indicator bolus compared to the Fermi model. In addition, the Bayesian approach provides additional interesting information such as the probability density function of the measurement and the uncertainty of the residual function, which makes it possible to know the reliability of the measurement carried out, in particular by observing the distribution of the probability density function of the measurement. Finally, we proposed an algorithm for segmentation of myocardial lesions, using the spatial and temporal dimensions of infusion data. This technique allows an objective and precise segmentation of the hypoperfused region allowing a measurement of myocardial blood flow over an area of tissue which behavior is homogeneous and which average signal measurement allows an increase in the contrast-to-noise ratio. In the cohort of 30 patients, the variability of myocardial blood flow measurements performed on voxels detected by this technique was significantly lower than that of measurements performed on voxels in manually defined areas (mean difference=0.14, 95% CI[0.07, 0.2]) and those performed on voxels in areas defined using the bullseye method (mean difference=0.25, 95% CI[0.17, 0.36])

Indiana University-Purdue University Indianapolis (IUPUI) / Atherosclerotic lesions of human beings are common diagnosed in regions of arte- rial branching and curvature. The prevalence of atherosclerosis is usually associated with hardening and ballooning of aortic wall surfaces because of narrowing of flow path by the deposition of fatty materials, platelets and influx of plasma through in- timal wall of Aorta. High Wall Shear Stress (WSS) is proved to be the main cause behind all these aortic diseases by physicians and researchers. Due to the fact that the atherosclerotic regions are associated with complex blood flow patterns, it has believed that hemodynamics and fluid-structure interaction play important roles in regulating atherogenesis. As one of the most complex flow situations found in cardio- vascular system due to the strong curvature effects, irregular geometry, tapering and branching, and twisting, theoretical prediction and in vivo quantitative experimental data regarding to the complex blood flow dynamics are substantial paucity. In recent years, computational fluid dynamics (CFD) has emerged as a popular research tool to study the characteristics of aortic flow and aim to enhance the understanding of the underlying physics behind arteriosclerosis. In this research, we study the hemo- dynamics and flow-vessel interaction in patient specific normal (healthy) and dilated (diseased) aortas using Ansys-Fluent and Ansys-Workbench. The computation con- sists of three parts: segmentation of arterial geometry for the CFD simulation from computed tomography (CT) scanning data using MIMICS; finite volume simulation of hemodynamics of steady and pulsatile flow using Ansys-Fluent; an attempt to perform the Fluid Structure Simulation of the normal aorta using Ansys-Workbench. Instead of neglecting the branching or smoothing out the wall for simplification as a lot of similar computation in literature, we use the exact aortic geometry. Segmen- tation from real time CT images from two patients, one young and another old to represent healthy and diseased aorta respectively, is on MIMICS. The MIMICS seg- mentation operation includes: first cropping the required part of aorta from CT dicom data of the whole chest, masking of the aorta from coronal, axial and saggital views of the same to extract the exact 3D geometry of the aorta. Next step was to perform surface improvement using MIMICS 3-matic module to repair for holes, noise shells and overlapping triangles to create a good quality surface of the geometry. A hexahe- dral volume mesh was created in T-Grid. Since T-grid cannot recognize the geometry format created by MIMICS 3-matic; the required step geometry file was created in Pro-Engineer. After the meshing operation is performed, the mesh is exported to Ansys Fluent to perform the required fluid simulation imposing adequate boundary conditions accordingly. Two types of study are performed for hemodynamics. First is a steady flow driven by specified parabolic velocity at inlet. We captured the flow feature such as skewness of velocity around the aortic arch regions and vortices pairs, which are in good agreement with open data in literature. Second is a pulsatile flow. Two pulsatile velocity profiles are imposed at the inlet of healthy and diseased aorta respectively. The pulsatile analysis was accomplished for peak systolic, mid systolic and diastolic phase of the entire cardiac cycle. During peak systole and mid-systole, high WSS was found at the aortic branch roots and arch regions and diastole resulted in flow reversals and low WSS values due to small aortic inflow. In brief, areas of sudden geometry change, i.e. the branch roots and irregular surfaces of the geom- etry experience more WSS. Also it was found that dilated aorta has more sporadic nature of WSS in different regions than normal aorta which displays a more uniform WSS distribution all over the aorta surface. Fluid-Structure Interaction simulation is performed on Ansys-WorkBench through the coupling of fluid dynamics and solid mechanics. Focus is on the maximum displacement and equivalent stress to find out the future failure regions for the peak velocity of the cardiac cycle.

Indiana University-Purdue University Indianapolis (IUPUI) / For years, the leading killer of Americans has been coronary artery disease (CAD), which has a strong correlation to the U.S. obesity epidemic. Obesity, along with the presence of other risk factors including hyperglycemia, hypercholesterolemia, dyslipidemia, and high blood pressure, comprise of the diagnosis of metabolic syndrome (MetS). The presentation of multiple MetS risk factors increases a patients risk for adverse cardiovascular events. CAD is a complex progressive disease. We utilized the superb model of CAD and MetS, the Ossabaw miniature swine, to investigate underlying mechanisms of CAD progression. We studied the influence of coronary epicardial adipose tissue (cEAT) and coronary smooth muscle cell (CSM) intracellular Ca2+ regulation on CAD progression. By surgical excision of cEAT from MetS Ossabaw, we observed an attenuation of CAD progression. This finding provides evidence for a link between local cEAT and CAD progression. Intracellular Ca2+ is a tightly regulated messenger in CSM that initiates contraction, translation, proliferation and migration. When regulation is lost, CSM dedifferentiate from their mature, contractile phenotype found in the healthy vascular wall to a synthetic, proliferative phenotype. Synthetic CSM are found in intimal plaque of CAD patients. We investigated the changes in intracellular Ca2+ signaling in enzymatically isolated CSM from Ossabaw swine with varying stages of CAD using the fluorescent Ca2+ indicator, fura-2. This time course study revealed heightened Ca2+ signaling in early CAD followed by a significant drop off in late stage calcified plaque. Coronary artery calcification (CAC) is a result of dedifferentiation into an osteogenic CSM that secretes hydroxyapatite in the extracellular matrix. CAC is clinically detected by computed tomography (CT). Microcalcifications have been linked to plaque instability/rupture and cannot be detected by CT. We used 18F-NaF positron emission tomography (PET) to detect CAC in Ossabaw swine with early stage CAD shown by mild neointimal thickening. This study validated 18F-NaF PET as a diagnostic tool for early, molecular CAC at a stage prior to lesions detectable by CT. This is the first report showing non-invasive PET resolution of CAC and CSMC Ca2+ dysfunction at an early stage previously only characterized by invasive cellular Ca2+ imaging.

Les patients atteints de stéatose hépatique non alcoolique (NAFLD) développent fréquemment des manifestations cardiovasculaires. Bien que souvent liées à l'obésité, ces anomalies peuvent également se développer chez des patients non obèses atteints de NAFLD impliquant que cette pathologie hépatique joue, en soi, un rôle dans la pathogenèse des complications cardiaques. Pour répondre à cette question et étudier les mécanismes sous-jacents indépendamment de toutes perturbations métaboliques et comorbidités préexistantes, nous avons utilisé un modèle murin arborant une déficience mitochondriale hépatique associée à un défaut d'assemblage du complexe IV de la chaîne respiratoire. Ce modèle murin avait préalablement été caractérisé au niveau hépatique mettant alors en évidence le développement d'une stéatose microvésiculaire et un profil lipidomique similaire à celui observé chez les patients atteints d'une NAFLD sans obésité. L'identification des mécanismes qui sous-tendent le développement et la progression de la NAFLD sans obésité et de ces répercussions extra-hépatiques ne faisant pas l'objet d'un très grand nombre d'études fondamentales, l'objectif principal était donc d'étudier l'axe foie-coeur. Dans le cadre des travaux de ce mémoire, nous avons cherché à approfondir la caractérisation hépatique, préalablement faite à l'âge de 5 semaines et ayant fait l'objet de publications par des laboratoires collaborateurs. Nous avons par la suite investigué la glycémie, l'insulinémie et le profil des lipoprotéines plasmatiques pour finir par l'analyse du métabolisme et de la fonction cardiaque. L'ensemble de ces expériences ont été faites en prenant en compte l'impact non négligeable du sexe sur la physiopathologie de la NAFLD. Nos résultats ont dévoilé un important remodelage phénotypique sexe-dépendant allant au-delà des lésions hépatiques. Les mâles un peu plus que les femelles présentaient une hypoglycémie à jeun et une sensibilité accrue à l'insuline. Ils présentaient un léger dysfonctionnement diastolique soutenu par un remodelage des lipoprotéines circulantes et dans une certaine mesure, par un remodelage du lipidome cardiaque. À l'inverse, les femelles ne manifestaient aucun dysfonctionnement cardiaque, mais présentaient des déficiences cardiométaboliques soutenues par une altération de l’intégrité et la fonction mitochondriale, un remodelage des lipoprotéines circulantes et une accumulation intracardiaque de triglycérides. À la lumière de ces résultats, cette étude souligne que les défauts métaboliques dans le foie peuvent entraîner des anomalies significatives et dépendantes du sexe affectant à la fois le phénotype mitochondrial/métabolique et la fonction contractile indépendamment de l'obésité. Ce modèle expérimental pourrait s'avérer utile dans la compréhension des mécanismes sous-jacents à la variabilité liée au sexe dans la progression de la NAFLD chez l'homme non obèse. / Cardiac abnormalities often develop in patients with non-alcoholic fatty liver disease (NAFLD). Although frequently linked to obesity, these abnormalities can also develop in patients with lean-NAFLD, implying that the liver pathology per se plays a role in the pathogenesis of cardiac complications. To address this question and investigate the underlying mechanisms independent of any pre-existent metabolic disruptions and comorbidities, we used a murine model of hepatic mitochondrial deficiency associated with a defect in the assembly of respiratory chain complex IV. This mouse model had previously been characterized at the hepatic level, showing the presence of microvesicular steatosis, and a lipidomic profile similar to that observed in patients with lean-NAFLD. Because few fundamental studies have adressed the identification of mechanisms underlying the development and progression of lean-NAFLD and its extrahepatic repercussions, the main aim was to study the liver-heart axis. As a part of this master's project, we sought to deepen the hepatic characterization of this mouse model, previously done at 5-weeks of age, and published by collaborators. We then investigated glycemia, insulinemia and plasma lipoprotein profile, and finally examined cardiac metabolism and function. All these experiments were done in consideration of the non-negligible impact of sexe on the pathophysiology of NAFLD. Our results unveiled a sex-dependent multi-faceted phenotypic remodeling that went beyond liver damage. Males, slightly more than females, showed fasting hypoglycemia and increased insulin sensitivity. They exhibited mild diastolic dysfunction supported by remodeling of the circulating lipoproteins, and to some extent remodeling of cardiac lipidome. Conversely, females did not manifest cardiac dysfunction, but exhibited cardiometabolic impairments supported by impaired mitochondrial integrity and function, remodeling of circulating lipoproteins, and intracardiac accumulation of triglycerides. In light of these findings, this study underscores that metabolic defects in the liver can result in significant sex-dependent abnormalities that affect both the mitochondrial/metabolic phenotype and contractile function independent of obesity. This experimental model may prove useful to better understand the mechanisms underlying the sex-related variability in the progression of lean-NAFLD in humans.

Text in Afrikaans / Coronary artery disease (CAD) is a life-threatening disease. When heart patients in the treatment of their disease, due to certain subjugating discourses practised by the biomedical model or biomedicine, are treated in a way that contributes to their anxiety and they feel themselves marginalised by society, then CAD becomes even more threatening. The narrative-pastoral approach of this study aims to treat heart patients in a way that has a calming effect on them that could assist them to deal with their heart disease more efficiently. This study shows how a heart patient's illness stories can be centralised by means of narrative therapy and how a pastoral and ethical attitude of love and respect can produce a climate that's conducive to better health and well-being. I indicate how my methodology of participatory action research succeeds in making the heart patients active participants to the research project. Their active participation indicates that meaning is not created on their behalf in therapy; rather, they are responsible for the process of richer construction of meaning. I describe how the participants socially co-constructed alternative and richer descriptions of their illness. Futhermore, I point out how their richer descriptions of illness contribute to perceptible and measurable results that are of value to the heart patients. / Koronere hartvatsiekte (KHS) is 'n lewensbedreigende siekte. Wanneer hartpasiente in die behandeling van hul siekte vanwee sekere onderdrukkende diskoerse van siekte vanuit die biomediese model of biomedisyne s6 hanteer word dat dit spanning op hul plaas en deur die samelewing gemarginaliseer word, word KHS des te meer gevaarlik. In hierdie studie gaan dit oor 'n narratief-pastorale benadering wat hartpasiente op 'n kalmerende manier hanteer sodat hulle kan kom tot 'n meer doeltreffende hantering van hul hartsiekte. Hierdie studie toon aan hoe hartpasiente se siekteverhale deur middel van narratiewe terapie gesentreer word en hoe 'n etiese en pastorale gesindheid van liefde en respek 'n klimaat skep wat bevorderlik is vir beter gesondheid en welwese. Ek dui aan hoe my metodologie van deelnemende aksienavorsing daarin geslaag het om die hartpasiente aktiewe deelnemers te maak aan die navorsingsprojek. Hul aktiewe deelname impliseer dat betekenis nie in terapie vir hulle geskep word nie, maar dat hulle self skeppend betrokke is in die proses van ryker betekeniskonstruering. Ek beskryf hoe die deelnemers altematiewe en ryker beskrywings van hul siekte sosiaal ko-konstrueer. Ek dui verder aan hoe hul ryker beskrywings van siekte bydra tot sigbare en meetbare resultate wat vir hartpasiente van waarde is. / Practical Theology / D. Th. (Praktiese Teologie)