Thesis (Ph. D.)--University of Missouri-Columbia, 2007. / The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. "December 2007" Includes bibliographical references.

Gene expression is regulated by local genetic sequence, and researchers have identified thousands of common genetic variants in the human population that associate with altered gene expression. These expression quantitative trait loci (eQTLs) often co-localize with genome wide association study (GWAS) loci, suggesting that they may hold the key to understanding genetic effects on human phenotype and cause disease. eQTLs are enriched in cis-regulatory elements, suggesting that many affect gene expression via non-coding mechanisms. However, many of the discovered loci lie in noncoding regions of the genome for which we lack understanding, and determining their mechanisms of action remains a challenge. To complicate matters further, genetic variants may have varied effects in different tissues or under different environmental conditions. The research presented here uses statistical methods to investigate genetic variants’ mechanisms of actions and context specificity. In Chapter 1, we introduce eQTLs and discuss challenges associated with their discovery and analysis. In Chapter 2, we investigate cross-tissue eQTL and gene expression patterns, including for GWAS genes. We find that eQTL effects show increasing, decreasing, and non-monotonic relationships with gene expression levels across tissues, and we observe higher eQTL effects and eGene expression for GWAS genes in disease-relevant tissues. In Chapter 3, we use the natural variation of transcription factor activity among tissues and between individuals to elucidate mechanisms of action of eQTL regulatory variants and understand context specificity of eQTL effects. We discover thousands of potential transcription factor mechanisms of eQTL effects, and we investigate the transcription factors’ roles with orthogonal datasets and experimental approaches. Finally, in Chapter 4, we focus on a locus implicated in coronary artery disease risk and unravel the likely causal variants and functional mechanisms of the locus’s effects on gene expression and disease. We confirm the locus’s colocalization with an eQTL for the LIPA gene, and using statistical, functional, and experimental approaches, we highlight two potential causal variants in partial linkage disequilibrium. Taken together, this work develops a framework for understanding eQTL context variability and highlights the complex genetic and environmental contributions to gene regulation. It provides a deeper understanding of gene regulation and of genetic and environmental contributions to complex traits and disease, enabling future research surrounding the context variability of genetic effects on gene expression and disease.

Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) är en arbetsdiagnos för patienter som söker med liknande symtom som vid akut koronart syndrom, EKG-förändringar samt troponinsläpp men utan att uppvisa signifikanta förträningar på kranskärlsröntgen som kan förklara patienternas symtom och kliniska fynd. Underliggande tillstånd kan vara alltifrån Takotsubo Syndrom (TS), myokardit, hjärtinfarkt till att inte kunna klarlägga bakomliggande orsak. Då entydig evidensbaserad forskning saknas kring denna patientgrupp finns således stora kunskapsluckor för hur vården ska samverka, inte minst vilka omvårdnadsåtgärder som specifikt behövs för dessa patienter. Enstaka studier har visat att ångest och depression återfinns i större grad hos patienter med MINOCA, vilket stimulerar till vidare forskning i ämnet. Om en riskgrupp kan identifieras i form av ångest eller depression, kan dessa patienter fångas upp och specifika omvårdnadsåtgärder utarbetas. Syftet med denna studie var att undersöka förekomst samt nivå av ångest och depression hos patienter som drabbas av MINOCA, vid insjuknandet och 12 månader efter diagnostisering. En kvantitativ forskningsansats med en icke-experimentell design användes och genomfördes med en prospektiv kohortstudie. Datainsamlingen utfördes med hjälp av Hospital Anxiety and Depression Scale (HADS), där deltagarna besvarade HADS-enkäten vid två upprepade tillfällen, vid insjuknande och 12 månader efter diagnostisering. Totalt skattade 127 deltagare sin grad av ångest och depression vid baseline och 67 deltagare efter 12 månader. Endast de deltagare som hade två uppföljande svarsvärden på HADS jämfördes över tid. Resultaten visade att vid insjuknandet sågs en signifikant lindrig till måttlig grad av ångest hos MINOCA-gruppen. Det var framförallt de patienter som drabbats av TS som uppvisade höga självskattningsvärden på HADS-A. Dessa patienter hade även kvarstående högt värde 12 månader efter diagnostisering. Däremot sågs ingen signifikant ökad grad av depression vid start eller efter 12 månader hos patienter med MINOCA. För patienter med hjärtinfarkt specifikt sågs lägre självskattningsvärden (ej signifikant) jämfört med övriga patienter. Denna studie, i likhet med andra studier, visar att många patienter som drabbas av MINOCA har en lindring till måttlig förekomst av ångest vid insjuknande. Det var framförallt de patienter som diagnostiseras med TS som skattade högst på HADS-A, både vid insjuknande och 12 månader efter diagnostisering. Resultatet indikerar att sjuksköterskor behöver utarbeta rutiner kring omhändertagandet av denna patientgrupp. Genom personcentrerad vård kan sjuksköterskor identifiera och uppmärksamma tecken på ångest eller nedstämdhet och stötta patienten. Sjuksköterskan kan också samla teamet kring patienten för att på bästa sätt identifiera och fånga upp faktorer som kan stärka patienten till förbättrat mående. Vidare forskning behövs för implementering av evidensbaserade åtgärder i vårdens dagliga arbete.

No description available.

Coronary stents have become a very popular treatment for cardiovascular disease, historically the leading cause of death in the United States. Stents, while successful in the short term, are subject to high failure rates (up to 24% in the first six months) due to wall regrowth and clotting, probably due to a combination of abnormal mechanical stresses and disruption of the arterial blood flow. The goal of this research was to develop recommendations concerning ways in which stent design might be improved, focusing on the problem of pressure wave reflections. A one-dimensional finite-difference model was developed to predict these reflections, and effects of variations in stent and vessel properties were examined, including stent stiffness, length, and compliance transition region, as well as vessel radius and wall thickness. The model was solved using a combination of Weighted Essentially Non-Oscillatory (WENO) and Runge-Kutta methods. Over 100 cases were tested. Results showed that reasonable variations in these parameters could induce changes in reflection magnitude of up to ±50%. It was also discovered that the relationship between each of these properties and the resulting wave reflection could be described simply, and the effect of all of them together could in fact be encompassed by a single non-dimensional parameter. This parameter was titled"Stent Authority," and several variations were proposed. It is believed this parameter is a novel way of relating the energy imposed upon the arterial wall by the stent, to the fraction of the incident pressure energy which is reflected from the stented region. / Master of Science

A hydraulic collapse mechanism was incorporated into a recirculating pulsatile flow system to simulate the physiologic problem cf coronary artery vasospasm. A dimensional analysis of the hemodynamic problem provided the basis for i) the specifications for elastic test sections (both straight and branching), ii) the determination of the flow modelling parameters, Reynolds number and unsteady Reynolds number, and iii) the determination of the dimensionless collapse parameters. The models were collapsed in a controlled manner while changes in volumetric flow rate into and out of the models as well as axial pressure drop were monitored. It was found that the driven collapse of the vessel acts as a pump, the effectiveness of which is dependent on upstream and downstream resistance. There was noted a difference in the volumetric flow curves representing fluid leaving the pre- and the post-collapse models under the same inflow conditions. This was due to both the elastic properties of the models and to the post-collapse shape of the models (curved walls and non-circular cross-section). Time-exposed photographs of tracer particle displacements within the model indicate increased volumetric flow in each branch during the initial phase of the collapse process. Moreover, it was seen that the radial gradient of the axial velocity at each wall surface varied in magnitude (and possibly in sign) during the collapse. The in vitro results do not substantiate the coronary spasm/myocardial ischemia connection, but do further implicate vasospasm as a factor in atherogenesis. / Ph. D.

Wall shear stress (WSS) has long been identified as a factor in the development of atherosclerotic lesions. Autopsy studies have revealed a strong tendency for lesion development at arterial branch sites and along the inner walls of curvature areas that, in theory, should experience low WSS. Calculations of coronary artery WSS have typically been based upon average models of coronary artery geometry with average flow conditions and then compared to average lesion distributions. With all the averaging involved, a more detailed knowledge of the correlation between WSS and atherosclerotic lesion development might be obscured. Recent advancements in hemodynamic modeling now enable the calculation of WSS in individual subjects. An image-based approach for patient-specific calculation of in vivo WSS using computational fluid dynamics (CFD) would allow a more direct study of this correlation. New state-of-the-art technologies in multi-detector computed tomography (CT) and 3.0 Tesla magnetic resonance imaging (MRI) offer potential improvements for the measurement of coronary artery geometry and blood flow. The overall objective of this research was to evaluate the quantitative accuracy of multi-detector CT and 3.0 Tesla MRI and incorporate those imaging modalities into a patient-specific CFD model of coronary artery WSS. Using a series of vessel motion phantoms, it has been shown that 64-detector CT can provide accurate measurements of coronary artery geometry for heart rates below 70 beats per minute. A flow phantom was used to validate the use of navigator-echo gated, phase contrast MRI at 3.0 Tesla to measure velocity of coronary blood flow. Patient-specific, time-resolved CFD models of coronary WSS were created for two subjects. Furthermore, it was determined that population-average velocity curves or steady state velocities can predict locations of high or low WSS with high degrees of accuracy compared to the use of patient-specific blood flow velocity measurements as CFD boundary conditions. This work is significant because it constitutes the first technique to non-invasively calculate in vivo coronary artery WSS using image-based, patient-specific modeling.

Atherothrombosis can induce acute myocardial infarction and stroke by progressive stenosis of a blood vessel lumen to full occlusion. The goal of this research is to determine what shear rates are pertinent to an occluding blood vessel, the rate of thrombus growth relative to wall shear rates, and to develop a predictive model for estimating length of time to thrombus occlusion for a given atherosclerotic lesion. Computational studies of severely stenotic idealized vessels were performed to investigate the wall shear rates that may exist. The study shows that maximum shear rates in severe short stenoses were found to exceed 250,000 1/s (9,500 dynes/cm2). We utilize an in vitro experiment consisting of blood flow through a collagen coated stenosis to study the rate of thrombus growth. Growth is monitored through light microscopy and a camera. Computational fluid dynamics are used to determine shear rates along the thrombus surface as it grows. We found a strong positive correlation between thrombus growth rates and shear rates up to 6,000 1/s after a log-log transformation (r=0.85, p<0.0001). Growth rates at pathologic shear rates were typically 2-4 times greater than for physiologic shear rates below 400 s-1. To determine whether transport or kinetic binding limits the rate of thrombus growth, a computational model of platelet transport was developed. The model allows for thrombus growth by occluding computational cells. We show that thrombus is transport rate-limited for shear rates below 6,000 1/s, while it is more likely to be kinetic rate-limited for higher shear rates. Predictions of occlusion times based on the model demonstrate that increases in stenosis severity results in decreased time to occlusion.

Vainikinių arterijų tyrimas daugiapjūviu kompiuteriniu tomografu (DKT) į klinikinę praktiką įdiegtas nesenai. Tai neinvazyvus tyrimo metodas, kurį galima atlikti ir ambulatoriniams pacientams. Tačiau greta savo privulumų, jis turi ir trūkumų – dėl nuolatinio vainikinių arterijų judėjimo širdies ciklo metu gali atsirasti liekamųjų judesio artefaktų atkuriant vaizdus. Jų tikimybė priklauso ne tik nuo aparato, kuriuo atliekamas tyrimas, techninių charakteristikų, bet ir nuo širdies veiklos ypatumų. Yra atlikta nemažai tyrimų, įvertinančių vainikinių arterijų vaizdų kokybės priklausomybę nuo širdies susitraukimų dažnio, jo variabilumo, kitų faktorių. Kairiosios Hiso pluošto kojytės blokados, sąlygojančios nesinchronišką skilvelių susitraukimą ir atsipalaidavimą, įtaka vaizdų kokybei tyrinėta mažai. Šiame tyrime buvo palyginta vaizdų kokybė tarp pacientų, kuriems nustatyta visiška kairiosios Hiso pluošto kojytės blokada ir nėra laidžiosios sistemos sutrikimų, grupių. Analizuota vainikinių arterijų įvertinimo visuose širdies ciklo rekonstrukciniuose intervaluose įtaka vaizdų kokybės vidurkiui. Nustatyta, kokia yra DKT tyrimo diagnostinė vertė identifikuojant hemodinamiškai reikšmingas vainikinių arterijų stenozes. Kadangi DKT tyrimas susijęs su jonizuojančia spinduliuote, įvertinti rentgeno vamzdžio srovės stiprumo moduliavimo ypatumai. Taip pat nustatyta širdies susitraukimų dažnio, jo variabilumo įtaka vaizdų kokybei, esant visiškai kairiosios Hiso pluošto kojytės blokadai. / Multislice computed tomography (MSCT) coronary angiography is one of the latest usage area of the computed tomography technology. It s a non-invasive diagnostic tool, wich can be performed in ambulant patients. MSCT coronary angiography beside it's advantages has some drawbacks. The main drawbacks are lower spatial resolution and residual motion artifacts in MSCT images. Therefore quality of coronary images and diagnostic value of MSCT angiography differs, depending on patient's clinical characteristics, especially on heart contraction features during scanning. Asynchronic contraction and relaxation of the right and left ventricles, caused of bundle branch block can also influence image quality of MSCT coronary angiography. To date, there are only few studies, conducted to analyse diagnostic performance of MSCT coronary angiography in patients with left bundle branch block. Although influence of heart rate, heart rate variability and the other factors (for example, age, sex, body mass index) on MSCT image quality are quite well investigated. Thus, the present study were designed to investigate the influence of complete left bundle branch block on image quality of MSCT coronary angiography more detail in comparison with control patients group without electrical conduction disturbances, reveal the diagnostic value of MSCT angiography to identify hemodinamicaly significant coronary stenosis.

Το θέμα της παρούσης εργασίας είναι η μελέτη της μη μόνιμης αιματικής ροής στις στεφανιαίες αρτηρίες της καρδιάς σε φυσιολογική κατάσταση, με στένωση καθώς και με αποκατάσταση της ροής με αναστομωτικό κλάδο. Για τον σκοπό αυτό χρησιμοποιούνται συμπεράσματα από τη διεθνή βιβλιογραφία γύρω από τους παράγοντες που μπορεί να οδηγήσουν στην ανάπτυξη στενώσεων, καθώς και κατευθυντήριες γραμμές για την διαμόρφωση των γεωμετρικών μοντέλων Στο πρώτο κομμάτι γίνεται μία αναφορά στις κυριότερες καρδιαγγειακές παθήσεις, που αποτελούν και την υπ αριθμόν ένα αιτία θανάτου παγκοσμίως. Γίνεται αναφορά στους επεμβατικούς τρόπους αντιμετώπισης της στεφανιαίας νόσου με έμφαση στην αορτοστεφανιαία παράκαμψη (bypass). Ακολουθεί μία σύντομη επισκόπηση της βιβλιογραφίας και εξαγωγή των βασικών συμπερασμάτων που θα αποτελέσουν την βάση για την κριτική των αποτελεσμάτων. Εν συνεχεία επεξηγείται αναλυτικά ο τρόπος με τον οποίο παράγονται τα γεωμετρικά μοντέλα, καθώς και οι περιπτώσεις που αναλύθηκαν. Ακολουθεί ο τρόπος κατασκευής του υπολογιστικού πλέγματος, πάνω στο οποίο επιλύονται οι εξισώσεις Navier- Stokes για ασυμπίεστο ρευστό. Τέλος με βάση τα αποτελέσματα από την εκτέλεση του κώδικα για όλες τις περιπτώσεις γίνεται μία προσπάθεια για εξαγωγή συμπερασμάτων. Εξάγονται με βάση την μελέτη των μοντέλων κάποιες ενδεικτικές κατευθυντήριες γραμμές ως προς το ποιες γεωμετρίες και τρόποι αναστόμωσης τείνουν να ευνοήσουν περισσότερο την ανάπτυξη της αθηρωματικής πλάκας αλλά και ποιες αποκαθιστούν την ροή του αίματος. / The subject of the following thesis is the study of the unsteady blood flow in the coronary arteries of the heart in normal conditions, during stenotic conditions and after restoration of the flow with an anastomotic branch. For this purpose, we use the conclusions from the international literature on the factors that can lead to the further development of stenoses, as well as guidelines on the formation of the geometrical models. In the first part we reference the most significant pathologic conditions of the heart which are the number one leading cause of death world widely. We also mention the invasive techniques with which doctors treat the coronary heart disease, emphasizing on the aorto-coronary bypass technique. Furthermore there is a review on the literature on the subject and extraction of the main conclusions we are going to use in the evaluation of the computational results We continue explaining in detail the way that the geometrical models where produced, as well as the cases which were analyzed. There is also an explanation of the way we constructed the computational grids on which we solve the incompressible Navier – Stokes equations. Finally, based on the computational results we obtain by executing the program for all the different cases we extract the basic conclusions. Based on the study of the models we try to give some basic guidelines regarding which geometries and anastomotic techniques tend to favor the further development of the atherosclerotic plaques , but also which ones restore the blood flow to the normal levels