C1q TNF Related Protein 3 (CTRP3) is a novel adipose tissue derived secreted factor, or adipokine, which has been linked to a number of beneficial biological effects on metabolism, inflammation, and survival signaling in a variety of tissues. However, very little is known about CTRP3 in regards to human health. The purpose of this project was to examine circulating CTRP3 levels in a clinical population, patients with symptoms requiring heart catheterization in order to identify the presence of obstructive coronary artery disease (CAD). It was hypothesized that serum CTRP3 levels would be decreased in the presence of CAD. Methods Body mass index (BMI), diabetes status, and plasma samples were collected from 100 patients who were >30 years of age and presented at the East Tennessee State University Heart Clinic with symptoms requiring heart catheterization in order to identify the presence of cardiovascular blockages (n = 52 male, n = 48 female). Circulating CTRP3 levels were quantified using commercially available ELISA. Results Circulating CTRP3 levels had no relationship to the presence of CAD regardless of gender. However, circulating concentrations of CTRP3 were significantly higher in normal weight (BMI < 30) females (0.88 ± 0.12 µg/ml) compared with males (0.54 ± 0.06 µg/ml). Further, obesity (BMI > 30) resulted in an increase in circulating CTRP3 levels in male subjects (0.74 ± 0.08 µg/ml) but showed a significant decrease in female subjects (0.58 ± 0.07 µg/ml). Additionally, there was a significant reduction in circulating CTRP3 levels in female subjects who were diagnosed with Type 2 diabetes compared with patients without (0.79 ± 0.08 vs. 0.42 ± 0.10 µg/ml). There was no relationship between diabetes status and circulating CTRP3 levels in male subjects. Conclusion Circulating CTRP3 levels had a different relationship with diabetes and obesity status between male and female patients. It is possible that circulating CTRP3 levels are controlled by hormonal status, however more research is needed to explore this relationship. Nevertheless, future studies examining the relationship between CTRP3 levels and disease status should treat gender as an independent variable.

Abdominal aortic aneurysms (AAAs), a permanent dilation in the abdominal region of the aorta, is a highly sexually dimorphic disease. AAAs prevalence is ranging from 4-10 fold higher in males than females. Defining the mechanistic basis for reduced (in females) or increased (in males) AAA formation and progression may uncover potential therapeutic targets. The majority of studies examining sexual dimorphism focus on the role of sex hormones. However, genes residing on sex chromosomes, in addition to sex hormones, may contribute to sexual dimorphism of AAAs. For example, the X chromosome contains about 5% of the whole genome, but the role of sex chromosomes genes to sexual dimorphism of cardiovascular diseases such as AAAs is largely unknown. The purpose of this study was to determine the role of sex chromosomes as mediators of sex differences for angiotensin II (AngII)-induced AAAs in hypercholesterolemic mice. We used the four core genotype murine model, which enables the creation of phenotypically normal male and female mice with an XX versus XY sex chromosome complement, to test the hypothesis that an XY sex chromosome complement promotes AngII-induced AAAs. Transgenic male mice expressing the Sry gene on an autosome, but not on the Y-chromosome, were bred to female low-density lipoprotein receptor deficient mice to create male and female mice with an XX or an XY sex chromosome complement. In females, an XY sex chromosome complement doubled the incidence and markedly increased the severity of AngII-induced AAAs. To define mechanisms, we examined gene expression patterns in abdominal aortas and demonstrated elevated expression of inflammatory genes that were linked to increased MMP activity and oxidative stress in aortas from XY females. Moreover, administration of testosterone to XY females, to mimic males, resulted in a striking level of aneurysm rupture. In males, transcriptional profiling of abdominal aortas revealed 450 genes that were influenced by sex chromosomes. Infusion of AngII to XY males resulted in diffuse pathology along the length of the aorta, while XX males developed focal AAAs, with pathology reduced by orchiectomy in both genotypes. Thoracic aortas of XY males exhibited adventitial thickening which was not exist in thoracic aortas from XX males. Following a prolonged period (3 months) of AngII infusions XY males had AAAs with expanded aortic walls, while XX males had thin walled dilated AAAs. In summary, our findings demonstrate a remarkable effect of sex chromosome complement to regulate aortic vasculature and disease development. Aside from demonstrating mechanisms of sexual dimorphism of aortic diseases, these findings indicate that chronic sex hormone therapy in the aging and transgender population may have cardiovascular ramifications. Moreover, identification of targets influenced by sex chromosomes and/or sex hormones in a manner that predicts disease development may identify sex-specific approaches to cardiovascular therapy.

Heart failure is a progressive condition that affects over 5.7 million Americans and costs associated with heart failure account for 2-3 % of the national health care budget. The high rates of morbidity and mortality along with increased costs from readmissions associated with advanced heart failure have led to the exploration of advanced treatments such as left ventricular assist devices (LVADs). LVADS have demonstrated morbidity and mortality benefit but cost remains extensive with costs per quality-adjusted years > $400,000. With this in mind, it is important to identify those who are most likely to benefit from an LVAD to avoid unfavorable outcomes and cost. Although general guidelines and criteria for patient eligibility have been established, choosing patients for LVAD implantation remains challenging. A new focus on patient selection involves the presence of frailty. While frailty has been studied in the elderly population and in patients undergoing cardiac surgery, frailty in patients undergoing left ventricular assist device (LVAD) remains controversial. The purpose of this dissertation was to examine measures of frailty in patients undergoing LVAD implantation. The specific aims of this dissertation were to: (1) identify a feasible frailty measure in adults with end-stage heart failure who underwent LVAD implantation by testing the hypothesis that frailty would predict 30 day rehospitalization rates using Fried’s criteria, Short Physical Performance Battery test, handgrip strength, serum albumin and six minute walk test (2) Determine whether frailty measures improve 3 months post LVAD implantation (3) compare sensitivity of these three measures to change in frailty. Surgical approaches, including heart transplantation and LVAD implantation, for patients with end-stage heart failure was discussed in this dissertation. Data from two subsets of participants who underwent LVADS at the University of Kentucky between 2014 and 2017 were included in the analysis for this dissertation. In the first study, we found that none of the measures are good predictors of frailty in patients with advanced heart failure who undergo LVAD implantation. Handgrip was the only marker of frailty that predicted 30 day readmission but the relationship was a negative association. In the second study, six-minute walk and low serum albumin levels reflect short-term improvement in frailty. These simple measures may be used to determine those patients who are responsive to LVAD implantation. The findings of these studies filled some gaps in our understanding of markers of frailty in patients undergoing LVADs. We gained a better understanding of which markers of frailty are likely to improve in most people after LVAD implantation and thus frailty should not preclude candidate selection for an LVAD. Subsequently, more research is needed to investigate these markers and outcomes.

To see if aggressive diuresis in first twenty four hours is associated with a comparable number of total days in the hospital as compared to non-aggressive diuresis. In this retrospective cohort study, we compared the length of hospital stay of consecutive patients admitted in one year based on their diuresis during the first twenty-four hours of hospitalization: aggressive diuresis (group 1) i.e. > 2400mL versus non-aggressive diuresis (group 2) i.e. ≤ 2400mL urine output. Patients were excluded if in cardiogenic shock, had creatinine level above 3 mg/dL on admission, or on dialysis. A total of 194 patients were enrolled (29 in group 1 and 165 in group 2 respectively). The Kaplan-Meier estimate of the median cumulative proportion of patients still hospitalized for the group 1 was 4 days and in group 2 was 5 days (log-rank test; P=0.67). In univariate analysis, Cox PH regression showed unadjusted hazard rate of discharge from hospital was slightly higher in group 1 than group 2 but was statistically non-significant (HR=1.08; P=0.70). In multivariate Cox model analysis, creatinine at the time of admission when greater than 1.6mg/dL (P=0.75), LVEF (P= 0.14), total twenty-four hours dose of intravenous Furosemide given (P=0.98) and interaction between Furosemide dose and Creatinine level (P=0.79) were not significant predictor of hospital discharge. Adjusted hazard rate for discharge from hospital was 12% higher in group 1 than group 2 but still statistically non-significant (HR=1.12; P=0.60). Since the length of hospital stay is similar between two groups, we suggest the goal of diuresis to be less than 2400mL in first twenty-four hours to prevent excessive dehydration.

Cancer (CA) is the second leading cause of death in the United States preceded only by cardiovascular disease (CVD). Over the past 30 years, the 5-year survival rate for all cancers combined has increased by more than 20%. This improved survival rate is due to early diagnosis and advances in treatment involving a multimodality treatment approach that includes radiotherapy [RT] with about half of all CA patients receiving some type of RT sometime during the course of their treatment. Cardiotoxicity is one of the most important adverse reactions of RT and leads to a meaningful risk of CVD-related morbidity and mortality. Radiotherapy-related cardiotoxicity is a heterogeneous clinical syndrome characterized by symptoms related to impaired cardiac function due to radiation-injury to one or more cardiac structures. Furthermore, the relative risk of CVD increases with increasing incidental radiation dose to the heart. There is not a unified consensus on the definition of CA-related cardiotoxicity although most trials have focused on changes in resting systolic function, and/or development of cardiac symptoms.Commonly used tools to assess cardiac function are insensitive to minor injury hence subtle changes may go unnoticed for many years. Cardiotoxicity definitions should include a dynamic functional assessment of the CV system. This may allow detection of latent CV abnormalities before the precipitous decline of resting myocardial function or the development of CV symptomology that may impact quality of life. Cardiopulmonary exercise testing (CPET) including measurement of peak oxygen consumption (VO2) is the gold standard for the assessment of cardiorespiratory fitness (CRF). Cardiorespiratory fitness is a strong, independent predictor of mortality, CVD-related mortality, HF-related morbidity and mortality, CA-related mortality and may be involved in the pathophysiologic link between anti-CA related treatments and the increased risk of late CVD events. Emerging evidence indicates CRF may be reduced in CA survivors and have utility to detect subclinical cardiotoxicity, but this has not been evaluated in CA survivors treated with RT with significant heart involvement. This dissertation consists of one literature review and one comprehensive paper that will examine the ability of CPET to detect subclinical cardiotoxicity.

Les arythmies auriculaires constituent une pathologie majeure en cardiologie, et leur étude constitue un vaste sujet de recherche. Pour les étudier, de nombreux modèles mathématiques de la propagation du potentiel d'action dans les oreillettes ont été développés. La plupart de ces modèles génériques permettent de reproduire des séquences d'activations typiques des oreillettes. De tels modèles peuvent avoir un intérêt expérimental, voir clinique, par exemple dans l'aide à la localisation des foyers arythmiques ou encore dans l'analyse des échecs du traitement de ces arythmies. Néanmoins, pour atteindre ce but, il faut être capable de recaler au mieux le modèle, dans ses dimensions géométriques ou fonctionnelles, sur des données individuelles. L'assimilation de données, discipline mathématique dans laquelle nous cherchons à combiner de manière optimale théorie et observations, est alors un bon candidat à la personnalisation des modèles de la propagation du potentiel d'action. Dans cette thèse, nous proposons d'étudier différentes méthodes d'assimilation de données -- séquentielles et variationnelles -- dans le but de combiner les modèles de propagation avec des données électroanatomiques. Plus précisément, nous nous intéressons à deux applications possible de l'assimilation de données que sont l'estimation d'état et l'estimation de paramètres. Dans un premier temps, nous étudions un observateur d'état permettant de corriger la position du front de propagation simulé en se basant sur la position du front observé. Cet observateur est alors utilisé afin de compléter une carte d'activation obtenue lors d'une procédure clinique. Ensuite, ce même observateur est combiné à un filtre de Kalman d'ordre réduit afin d'estimer les paramètres de conductivités du modèle mathématique de propagation du potentiel d'action. Une étude de la stratégie d'estimation liée état-paramètre est ensuite réalisée pour voir comment la méthode se comporte face aux erreurs de modélisation. La méthode est ensuite testée sur un jeu de données acquis cliniquement. Puis, nous regardons du côté des méthodes d'assimilation de données variationnelles qui permettent l'estimation de paramètres spatialement distribués. Plusieurs problèmes de minimisation, permettant d'estimer un paramètre de conductivité distribué dans l'espace, sont alors introduits et analysés. Nous montrons alors que la discrétisation de ces problèmes de minimisation, dans le but d'obtenir des méthodes numériques de résolution, peut s'avérer complexe. Une méthode numérique est ensuite mise en place pour un des problèmes de minimisation étudié, et trois cas tests unidimensionnels sont analysés.Enfin, nous démontrons l'existence d'un minimum pour une des fonctions objectif étudiées en nous basant sur des résultats d'analyse fonctionnelle de la littérature. / Atrial arrhythmias are a major pathology in cardiology, and their study is alarge research topic. To study them, many mathematical models of the actionpotential propagation in atria have been developed. Most of those generic models can be used to reproduce typical activation sequences of the atria. Such models may have an experimental or even clinical interest, for example in helping the location of arrhythmic foci or in the analysis of treatment failures for these arrhythmias. Nevertheless, to achieve this goal, it isnecessary to be able to adjust the model at best, based on experimental orclinical data. Data assimilation, a mathematical discipline in which we seek to optimally combine theory and observations, is then a good candidate for the customization of action potential propagation models.In this thesis, we propose to study different data assimilation methods-- sequential and variational -- in order to adjust action potential propagation model on electroanatomical data. More precisely, we are interested in two possible applications of data assimilation: state estimation and parameter estimation.First, we study a state observer which is able to correct the simulatedpropagation front localization based on the observed front localization. Thisobserver is then used to complete an activation map obtained during a clinical procedure.Then, this observer is combined with a reduced order Kalman filterin order to estimate the conductivity parameters of the action potentialpropagation model. A study of the joint state-parameter estimationstrategy is then realized to see how the method behaves faced with modelingerrors. The method is then tested on a clinically acquired dataset.Then, we look at variational data assimilation methods that allow the estimation of spatially distributed parameters. Several minimization problems, allowing to estimate a conductivity parameter distributed in space, are then introduced and analyzed. We then show that the discretization of these minimization problems, in order to obtain numerical methods of resolution, can be complex. A numerical method is then implemented for one of the studied minimization problems, and three 1D test cases are analyzed.Finally, we demonstrate the existence of a minimum for one of the studiedobjective function based on functional analysis results from theliterature.

<p>The substantial advances of coronary CTA have resulted in a boost of use of this new technique in the last several years, which brings a big challenge to radiologists by the increasing number of exams and the large amount of data for each patient. The main goal of this study was to develop a computer tool to facilitate coronary CTA analysis by combining knowledge of medicine and image processing.Firstly, a competing fuzzy connectedness tree algorithm was developed to segment the coronary arteries and extract centerlines for each branch. The new algorithm, which is an extension of the “virtual contrast injection” method, preserves the low density soft tissue around the coronary, which reduces the possibility of introducing false positive stenoses during segmentation.Secondly, this algorithm was implemented in open source software in which multiple visualization techniques were integrated into an intuitive user interface to facilitate user interaction and provide good over¬views of the processing results. Considerable efforts were put on optimizing the computa¬tional speed of the algorithm to meet the clinical requirements.Thirdly, an automatic seeding method, that can automatically remove rib cage and recognize the aortic root, was introduced into the interactive segmentation workflow to further minimize the requirement of user interactivity during post-processing. The automatic procedure is carried out right after the images are received, which saves users time after they open the data. Vessel enhance¬ment and quantitative 2D vessel contour analysis are also included in this new version of the software. In our preliminary experience, visually accurate segmentation results of major branches have been achieved in 74 cases (42 cases reported in paper II and 32 cases in paper III) using our software with limited user interaction. On 128 branches of 32 patients, the average overlap between the centerline created in our software and the manually created reference standard was 96.0%. The average distance between them was 0.38 mm, lower than the mean voxel size. The automatic procedure ran for 3-5 min as a single-thread application in the background. Interactive processing took 3 min in average with the latest version of software. In conclusion, the presented software provides fast and automatic coron¬ary artery segmentation and visualization. The accuracy of the centerline tracking was found to be acceptable when compared to manually created centerlines.</p>

<p>Kvantifisering av hjertets muskelfunksjon med tøyning og tøyningshastighet målt med ultralyd for vurdering av koronar sykdom.</p><p>Automatisert metode versus manuell ved akutt hjerteinfarkt og ultralyd stress test.</p><p>Vanligvis måles hjertets muskelfunksjon med ultralyd, en mye brukt metode for å diagnostisere hjertesykdommer. Vurderingen av muskelfunksjonen baserer seg i dag på en subjektiv visuell gradering av bevegelsen av hjertemuskelen, og dette krever erfaring. En ny automatisert diagnostisk ultralydsmetode basert på måling av hastigheten i hjertemuskelen gir et kvantitativt mål på muskelens tøyning og sammentrekning. Den nye metoden gir ny og mer detaljert informasjon om hjertets funksjon og om pasientens prognose enn vanlig ultralydsvurdering.</p><p>Den nye metoden er mer presis ved oppfølgning etter hjerteinfarkt. Et hjerteinfarkt gir nedsatt bevegelse av muskelen og måles med den nye metoden som nedsatt hastighet som muskelen forkortes med. Små forandringer i den skadde hjertemuskelen, ikke alltid synlige for øyet, kan mer nøyaktig følges over tid med den nye metoden. Utbredelsen av hjerteinfarktet kan også vurderes mer nøyaktig.</p><p>Det samme gjelder når angina vurderes under belastning. Når en pasient ikke kan sykle eller gå på tredemølle brukes en medisinsk belastningstest. Ved å belaste hjertet med et medikament som øker hjertemuskelens arbeid samtidig med en ultralydundersøkelse, kan vi oppdage redusert blodforsyningsreserve i hjertet. Stresstesten hjelper til med å vurdere om en trang blodåre bør åpnes etter et hjerteinfarkt, og til å vurdere pasienters risiko for hjertekomplikasjoner før en større operasjon. Den nye metoden gir i tillegg mer informasjon om den langsiktige prognosen sammenlignet med den gamle metoden. Vi har funnet at den nye ultralydsmetoden er mer presis (gir større diagnostisk treffsikkerhet i diagnostikk av koronarsykdom) sammenlignet med den gamle.</p><p>Måling av sammentrekningshastigheter i hjertemuskelen ble utviklet og testet på Institutt for sirkulasjon og bildediagnostikk ved NTNU av Andreas Heimdal og Asbjørn Støylen i 1998. Metoden trengte teknisk videreutvikling og testing i et større pasientmateriale. Metoden har ikke fått stor utbredelse på sykehusene pga støyfylte kurver og tidskrevende analyser, men med denne automatiserte metoden blir brukervennligheten større som muliggjør klinisk bruk.</p> / Paper I and II preprinted with kind permission of Elsevier, sciencedirect.com

<p>Uppsatsens syfte är att undersöka vilka ekonomiska effekter införandet av distansuppföljning för ICD-patienter har ur ett samhällsperspektiv. Delsyftet är att identifiera ekonomiska argument och kvalitativa aspekter för och emot införandet av tjänsten distansuppföljning.</p><p>Författarna har kommit fram till ett antal slutsatser. Att införa distansuppföljning som uppföljningsmetod för ICD-patienter istället för konventionella återbesök på sjukhus innebär stora kostnadsbesparingar. Nettonuvärdet uppgår till drygt 268 miljoner kronor efter femton år. Vid tidsperiodens slut erhålls en kostnadsbesparing på cirka 35,6 procent. De ekonomiska fördelarna överstiger kostnaderna redan efter ett år, och hela investeringskostnaden återfås efter sju år. Kvalitativa argument som talar för distansuppföljning är tidsbesparingar, förenklad uppföljning, bättre övervakning och att patienterna upplever en större trygghet.</p>

Thesis (Ph. D.)--Ohio State University, 2006. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2007 Sep 12