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.

Objetivo: Estimar o volume placentário e os índices de vascularização placentária em gestantes com síndromes hipertensivas, no segundo e terceiro trimestres gestacionais, e compará-los com os de gestantes sem morbidades (grupo controle). Métodos: Durante o período compreendido entre Abril de 2011 a Julho de 2012, foi realizado estudo clínico, prospectivo caso-controle envolvendo 62 gestantes hipertensas com idades gestacionais compreendidas entre 27 a 38 semanas e 66 gestantes hígidas na mesma faixa de idade gestacional. As gestantes foram submetidas à ultrassonografia para avaliação do volume placentário tridimensional calculado pelo método VOCAL, analisado mediante dois índices placentários, ou seja, volume placentário observado sobre esperado (VP o/e) e relação entre volume placentário sobre peso fetal (VP/PF), e também com quantificação da vascularização placentária por meio dos índices vasculares: índice de vascularização (IV), índice de vascularização e fluxo (IVF) e índice de fluxo (IF), utilizando ultrassom 3D power Doppler. Os critérios de inclusão foram gestações únicas com idade gestacional confirmada à ultrassonografia, sem malformações fetais e com diagnóstico do tipo de hipertensão, realizado segundo os critérios seguidos pelo protocolo assistencial da Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo ou gestações sem complicações clínicas e/ou obstétricas. Foram assim criados dois índices placentários: de volume placentário observado (calculado no exame) sobre a média esperada (percentil 50 da curva de normalidade publicada por de Paula et al.),definido pela sigla VP o/e; e um índice relacionando o volume placentário estimado sobre o peso fetal, definido pela sigla VP/PF; este último com o objetivo de eliminar a influência da variável Idade gestacional. Resultados: Foram incluídas no estudo 62 gestantes hipertensas (grupo estudo) e 66 gestantes hígidas (grupo controle). Do total de pacientes examinadas, 7 ( 5,4 %) foram excluídas: 6 por apresentarem intercorrências clínicas maternas e 1 por óbito fetal. Não houve diferenças estatisticamente significativas entre os índices de volumes placentários (O/E VP e VP/PF) das pacientes do grupo estudo quando comparadas com o grupo controle (p=0,793 e 0,152, respectivamente). Em relação aos índices vasculares placentários, houve redução significativa do IV (p < 0,001) e do IVF (p=0,002), não tendo havido redução nos valores do IF.Em relação a esse índice houve aumento do valor do fluxo, com p=0,006. Conclusão: Os volumes placentários não apresentaram diferenças estatisticamente significativas quando comparados com os de pacientes do grupo controle. Os índices de vascularização placentária (IV, IF e IVF) apresentaram os seguintes resultados: o IV e o IVF se mostraram significativamente menores nas pacientes hipertensas, enquanto o IF não mostrou redução no grupo estudo quando comparados com os do controle / Objectives: Our aim was to estimate placental volumes and vascular indexes in pregnant women with hypertensive syndromes during second and third gestational trimesters, and to compare them with those of healthy pregnant women (control group). Methods: From April 2011 to July 2012 a clinical, prospective, case-control study has been performed with 62 hypertensive pregnant women at gestational age of 27 to 38 weeks and 66 healthy pregnant women at the same gestational age. All pregnant women underwent three-dimensional power Doppler ultrasound examination to assess the placental volumes and vascular indexes: VI (vascularization Index), Vascularization Flow Index (VFI) and Flow Index (FI). The inclusion criteria were single gestation with gestational age confirmed by first trimester ultrasound, without fetal malformations and established diagnosis of hypertension according to criteria used at Obstetrics Department from Hospital das Clinicas of Faculdade de Medicina da Universidade de São Paulo or pregnant women without clinical diseases or obstetrical complications. Two placental volume ratios were created: observed-toexpected placental volume (o/e-PV) and placental volume-to-estimated fetal weight (PV/EFW) aiming to exclude any influence of the gestational age over results. For expected placental volume we used the 50th percentile from placental volume normograms as published by de Paula et al. Results Sixtysix healthy pregnant women and 62 pregnant women with hypertensive disorders were evaluated (matched by maternal age, gestational age at ultrasound exam and parity). Placental volumes were not reduced in pregnancy with hypertensive disorders (p>0.05). Reduced placental VI and VFI were observed in pregnancy complicated with hypertensive disorder (p<0.01 and p<0.01), specially in patients with superimposed preeclampsia (p=0.02 and 0.04). Week correlation was observed between placental volumes, placental vascular indices and Doppler studies of the uterine and umbilical arteries. Conclusion: Placental volumes showed no statistically significant differences when comparing study group with control group. Vascularization indices (VI, FI and VFI) have showed the following results: VI and VFI were significantly lower in hypertensive patients, whilst FI showed no decrease when compared to control group

Objetivo: Estimar o volume placentário e os índices de vascularização placentária em gestantes com síndromes hipertensivas, no segundo e terceiro trimestres gestacionais, e compará-los com os de gestantes sem morbidades (grupo controle). Métodos: Durante o período compreendido entre Abril de 2011 a Julho de 2012, foi realizado estudo clínico, prospectivo caso-controle envolvendo 62 gestantes hipertensas com idades gestacionais compreendidas entre 27 a 38 semanas e 66 gestantes hígidas na mesma faixa de idade gestacional. As gestantes foram submetidas à ultrassonografia para avaliação do volume placentário tridimensional calculado pelo método VOCAL, analisado mediante dois índices placentários, ou seja, volume placentário observado sobre esperado (VP o/e) e relação entre volume placentário sobre peso fetal (VP/PF), e também com quantificação da vascularização placentária por meio dos índices vasculares: índice de vascularização (IV), índice de vascularização e fluxo (IVF) e índice de fluxo (IF), utilizando ultrassom 3D power Doppler. Os critérios de inclusão foram gestações únicas com idade gestacional confirmada à ultrassonografia, sem malformações fetais e com diagnóstico do tipo de hipertensão, realizado segundo os critérios seguidos pelo protocolo assistencial da Clínica Obstétrica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo ou gestações sem complicações clínicas e/ou obstétricas. Foram assim criados dois índices placentários: de volume placentário observado (calculado no exame) sobre a média esperada (percentil 50 da curva de normalidade publicada por de Paula et al.),definido pela sigla VP o/e; e um índice relacionando o volume placentário estimado sobre o peso fetal, definido pela sigla VP/PF; este último com o objetivo de eliminar a influência da variável Idade gestacional. Resultados: Foram incluídas no estudo 62 gestantes hipertensas (grupo estudo) e 66 gestantes hígidas (grupo controle). Do total de pacientes examinadas, 7 ( 5,4 %) foram excluídas: 6 por apresentarem intercorrências clínicas maternas e 1 por óbito fetal. Não houve diferenças estatisticamente significativas entre os índices de volumes placentários (O/E VP e VP/PF) das pacientes do grupo estudo quando comparadas com o grupo controle (p=0,793 e 0,152, respectivamente). Em relação aos índices vasculares placentários, houve redução significativa do IV (p < 0,001) e do IVF (p=0,002), não tendo havido redução nos valores do IF.Em relação a esse índice houve aumento do valor do fluxo, com p=0,006. Conclusão: Os volumes placentários não apresentaram diferenças estatisticamente significativas quando comparados com os de pacientes do grupo controle. Os índices de vascularização placentária (IV, IF e IVF) apresentaram os seguintes resultados: o IV e o IVF se mostraram significativamente menores nas pacientes hipertensas, enquanto o IF não mostrou redução no grupo estudo quando comparados com os do controle / Objectives: Our aim was to estimate placental volumes and vascular indexes in pregnant women with hypertensive syndromes during second and third gestational trimesters, and to compare them with those of healthy pregnant women (control group). Methods: From April 2011 to July 2012 a clinical, prospective, case-control study has been performed with 62 hypertensive pregnant women at gestational age of 27 to 38 weeks and 66 healthy pregnant women at the same gestational age. All pregnant women underwent three-dimensional power Doppler ultrasound examination to assess the placental volumes and vascular indexes: VI (vascularization Index), Vascularization Flow Index (VFI) and Flow Index (FI). The inclusion criteria were single gestation with gestational age confirmed by first trimester ultrasound, without fetal malformations and established diagnosis of hypertension according to criteria used at Obstetrics Department from Hospital das Clinicas of Faculdade de Medicina da Universidade de São Paulo or pregnant women without clinical diseases or obstetrical complications. Two placental volume ratios were created: observed-toexpected placental volume (o/e-PV) and placental volume-to-estimated fetal weight (PV/EFW) aiming to exclude any influence of the gestational age over results. For expected placental volume we used the 50th percentile from placental volume normograms as published by de Paula et al. Results Sixtysix healthy pregnant women and 62 pregnant women with hypertensive disorders were evaluated (matched by maternal age, gestational age at ultrasound exam and parity). Placental volumes were not reduced in pregnancy with hypertensive disorders (p>0.05). Reduced placental VI and VFI were observed in pregnancy complicated with hypertensive disorder (p<0.01 and p<0.01), specially in patients with superimposed preeclampsia (p=0.02 and 0.04). Week correlation was observed between placental volumes, placental vascular indices and Doppler studies of the uterine and umbilical arteries. Conclusion: Placental volumes showed no statistically significant differences when comparing study group with control group. Vascularization indices (VI, FI and VFI) have showed the following results: VI and VFI were significantly lower in hypertensive patients, whilst FI showed no decrease when compared to control group

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.

RESUME DES TRAVAUX<p><p>La rigidification des gros troncs artériels (GTA) est physiologiquement liée à l’âge et s’accélère sous l’influence de certains facteurs de risque cardiovasculaire tels que l’hypertension artérielle (HTA), le diabète, le tabagisme, la dyslipidémie, l’obésité, la consommation excessive de sel, la sédentarité et l’hérédité. Le vieillissement artériel prématuré est un déterminant majeur du risque d’événements cardiovasculaires. Il se caractérise par une altération des propriétés élastiques des GTA, consécutive à l’épaississement de l’intima et surtout de la média se traduisant par une rigidification de leur paroi et une intensification de la réflexion de la courbe de pression aortique. Une artère rigide accélère la vitesse de propagation de l’onde de pouls (VOP) qui en est le marqueur direct et induit par conséquent un retour plus précoce des ondes de pression réfléchies de la périphérie vers l’aorte.<p>Nous avons testé l’hypothèse que le risque accru de maladies cardiovasculaires (MCV) documenté chez les sujets noirs africains serait lié en partie au vieillissement précoce de leurs artères et que son amplification chez les bantous serait largement attribuable aux facteurs environnementaux.<p>A cet effet, nous avons procédé dans un premier temps à la validation de la VOP, de la pression pulsée (pression systolique-pression diastolique) et de l’index d’augmentation de pression (AIx), tous deux dérivés de la courbe de pression aortique comme méthodes de mesure et d’évaluation non invasive de la distensibilité artérielle chez les sujets normotendus. Nos résultats révèlent que la stimulation bêta-adrénergique non cardio-sélective par l’isoproterenol atténue de façon significative la réflexion des ondes de pression aortique et augmente nettement la pression pulsée (PP) aortique alors que la VOP aortique qui constitue la mesure de référence de l’élasticité artérielle n’est pas affectée. Ces résultats suggèrent dès lors que la PP et l’AIx ne sont pas des marqueurs fiables de la rigidité artérielle lors de la stimulation bêta-adrénergique.<p><p>Nous avons ensuite évalué l’amplitude de cet effet de l’isoproterenol sur la paroi artérielle du sujet noir africain. C’est ainsi que nous avons observé que la stimulation bêta-adrénergique par l’isoproterenol engendre une accélération de la VOP aortique chez les sujets noirs, contrairement aux sujets caucasiens chez qui elle la ralentit considérablement. Ce résultat suggère que l’altération précoce des propriétés structurelles et fonctionnelles de la paroi aortique des sujets noirs sous l’effet de divers stress pourrait contribuer à la sévérité et à la précocité des MCV couramment rapportées au sein de ce groupe ethnique.<p><p>Nous avons ensuite testé une série d’hypothèses nécessitant des mesures non invasives de l’élasticité artérielle au sein de populations particulières au Cameroun.<p>C’est ainsi que nous avons investigué l’effet de l’anémie falciforme sur la rigidité artérielle et la réflexion de la courbe de pression aortique. L’hypothèse testée était que les complications cardiovasculaires couramment rapportées chez les drépanocytaires seraient dues à l’altération des propriétés viscoélastiques de leur paroi artérielle. Cette seconde partie de nos travaux nous a permis de démontrer que les patients drépanocytaires souffrant de la forme homozygote d’anémie falciforme (SS) ont des artères centrales aortiques très souples et des artères périphériques musculaires moins rigides. En effet, leur VOP est ralentie et leurs ondes de réflexion de la périphérie vers l’aorte sont fortement atténuées en comparaison aux contrôles sains (AA). L’anémie falciforme et la pression artérielle moyenne (PAM) sont apparues comme étant des déterminants indépendants de l’état d’élasticité aortique dans notre population d’étude (SS et AA). Cette étude a révélé toutefois une accélération paradoxale des VOP radiale et aortique dans les zones de basse pression artérielle, suggérant un effet délétère vasculaire de l’hypotension artérielle sévère chronique sur la paroi aortique.<p><p>Enfin, dans le troisième volet de notre travail, nous avons évalué l’effet du mode de vie chasseurs-pêcheurs-cueilleurs sur l’état d’élasticité aortique des pygmées traditionnels (TP) Camerounais. Nos travaux révèlent que ces TP ont des artères plus élastiques illustrées par une faible accélération de leur VOP aortique, comparée à celles des pygmées contemporains (CP) et des agriculteurs bantous partageant le même environnement semi-urbain et soumis tous à un mode de vie de type occidental. Fait important, cette faible accélération de la VOP aortique des TP est indépendante de la PAM et de leur âge chronologique qui en constituent pourtant des déterminants majeurs classiques bien documentés. Par contre, cette différence d’élasticité aortique entre TP, CP et bantous s’estompe nettement après correction pour le poids corporel.<p>Dans le même ordre d’idées, nous avons également démontré qu’en dépit de leur petite taille, les pygmées traditionnels réfléchissent leurs ondes de pression de la périphérie vers l’aorte avec une amplitude similaire à celle des pygmées contemporains et des bantous semi urbains.<p><p> <p>Conclusion.<p>Les résultats de nos travaux confortent la VOP comme marqueur de référence de la rigidité artérielle et suggèrent un vieillissement précoce de l’aorte chez les sujets noirs pouvant expliquer en partie la sévérité et la précocité des MCV couramment rapportées chez eux. Ce phénomène s’illustre notamment par l’accélération de la VOP aortique induite par l’isoproterenol chez les sujets noirs africains contrairement aux sujets caucasiens, chez qui la stimulation bêta-adrénergique par isoproterenol s’accompagne d’un ralentissement considérable de la VOP aortique. Cependant, l’état drépanocytaire pourrait atténuer et ralentir ce phénomène de vieillissement vasculaire précoce, ceci en dépit d’une accélération paradoxale de la VOP par l’hypotension artérielle chronique. Enfin, le mode de vie chasseurs-pêcheurs-cueilleurs protègerait l’aorte des pygmées traditionnels contre le risque de vieillissement prématuré, ceci indépendamment de la pression artérielle moyenne et de l’âge chronologique.<p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Hintergrund und Fragestellung Um den Zeitpunkt des Beginns der Datenakquisition bei der CT-Koronarangiographie festzulegen, bietet die Methode des Bolus-Trackings eine weit verbreitete Möglichkeit. Hierfür muss eine sogenannte Region of Interest (ROI) festgelegt werden, in der die Kontrastmittelanflutung gemessen wird. Bisher wurden die Auswirkungen unterschiedlicher Positionierungen dieser ROI auf die Bildqualität der Koronararterien (Hauptstamm der linken Koro-nararterie: LM; rechte Koronararterie: RCA) noch nicht systematisch untersucht. Zwei häufig verwendete Positionen sind der linke Herzvorhof (LV) und die Aorta ascendens (AA). Diese Positionierungen sollten in dieser Studie verglichen werden. Auch bei der Triple-Rule-Out-CT-Angiographie (TRO-CTA), in der zusätzlich zu den Koronararterien auch die Pulmonalarterien sowie die thorakale Aorta beurteilt werden sollen, kommt das Bolus-Tracking zur Anwendung. Die ROI wird hierbei meist im linken Herzvorhof positioniert. Da bisher nicht gezeigt wurde, ob die Pulmonalarterien (rechte Pulmonalarterie: RPA; linke Pulmonalarterie: LPA) dadurch tatsächlich in besserer Qualität dargestellt werden, sollte auch diese Frage in der Studie beantwortet werden. Methode Alle Patienten der vorliegenden monozentrischen, retrospektiven Studie erhielten eine CT-Koronarangiographie im Step-and-Shoot-Modus zum Ausschluss einer koronaren Herzkrankheit bei intermediärem Risiko. Mittels Propensity-Score-Matching wurden insgesamt 192 Patienten für die Studie ausgewählt: je 96 mit Positionierung der ROI im linken Vorhof bzw. in der Aorta ascendens (122 männliche und 70 weibliche Patienten, Alter 21 bis 87 Jahre, Durchschnittsalter 61 Jahre). Um möglichst ähnliche Patientencharakteristika in beiden Gruppen zu erreichen, wurden beim Propensity-Score-Matching folgende Faktoren berücksichtigt: Geschlecht, Körpergröße, Körpergewicht und Herzfrequenz. Für die Beurteilung der Bildqualität wurden sowohl ein quantitativer als auch ein qualitativer Score verwendet. Bei der quantitativen Analyse wurden die Signalintensitäten sowie deren Standardabweichungen in den zu beurteilenden Strukturen gemessen und daraus die Signal-Rausch-Verhältnisse (SNR) errechnet. Die qualitative Auswertung wurde von zwei Fachärzten für Radiologie mit 10 bzw. 6 Jahren Erfahrung in der CT-Koronarangiographie unabhängig voneinander mit Hilfe einer 5-Punkte-Likert-Skala durchgeführt. So wurde zum einen die Qualität der Darstellung der Koronararterien verglichen, zum anderen die der Pulmonalarterien. Für die statistische Auswertung wurde der Wilcoxon-Test verwendet, um die quantitativen sowie qualitativen Scores beider Patientengruppen miteinander zu vergleichen. Außerdem wurde bezüglich der qualitativen Analyse die Interrater-Reliabilität mittels gewichtetem Cohens Kappa (κ) bestimmt. Zusätzlich wurde die Strahlenbelastung beider Gruppen durch die Betrachtung der Dosis-Längen-Produkte sowie die Berechnung der effektiven Dosen verglichen. Ergebnisse Bezüglich der Koronararterien fanden sich sowohl beim Vergleich der quantitativen (SNR AA 14.92 vs. 15.46; p = 0.619 | SNR LM 19.80 vs. 20.30; p = 0.661 | SNR RCA 24.34 vs. 24.30; p = 0.767) als auch der qualitativen Scores (4.25 vs. 4.29; p = 0.672) keine signifikanten Unterschiede in beiden Gruppen. Für die Darstellung der Pulmonalarterien hat die Position der ROI allerdings eine entscheidende Bedeutung. Bei einer Positionierung im linken Vorhof ergeben sich signifikant höhere quantitative (SNR RPA 8.70 vs. 5.89; p < 0.001 | SNR LPA 9.06 vs. 6.25; p < 0.001) und auch qualitative Scores (3.97 vs. 2.24; p < 0.001) als bei einer Positionierung in der Aorta ascendens. Bezüglich der Interrater-Reliabilität konnte in dieser Studie eine beachtliche Konkordanz bei der Analyse der Koronararterien (κ = 0.654) bzw. eine nahezu vollkommene Konkordanz bei der Analyse der Pulmonalarterien (κ = 0.846) festgestellt werden. Die Strahlenbelastung war in beiden Gruppen nahezu identisch (4.13 mSv vs. 4.13 mSv; p = 0.501). Schlussfolgerung Für CT-Angiographien mit ausschließlich koronarer Indikation bedeutet dieses Ergebnis, dass die Positionierung der ROI für das Bolus-Tracking in der Aorta ascendens bzw. im linken Herzvorhof zu gleichwertigen Ergebnissen bezüglich der Bildqualität führen und somit die aktuell von vielen Untersuchern bevorzugte Positionierung der ROI in der Aorta ascendens weiterhin angewendet werden kann. Außerdem wurde in dieser Studie nachgewiesen, dass eine Positionierung der ROI im linken Herzvorhof zu einer besseren Beurteilbarkeit der Pulmonalarterien führt und deshalb bei der TRO-CTA angewendet werden sollte. Das Ergebnis zeigt aber auch, dass diese bei der TRO-CTA übliche Positionierung im linken Herzvorhof die Abbildung der Koronararterien nicht beeinträchtigt und der Einsatzbereich der TRO-CTA somit weiter ausgedehnt werden kann. / Background, aims and objectives The bolus tracking technique is widely used for choosing the optimal starting point of data acquisition in coronary computed tomography angiography (CCTA) scans. It utilizes repeated scans at a predefined position in order to determine the concentration of contrast media in a region of interest (ROI). The scan starts automatically when a trigger threshold is reached. The effect by different ROI positioning on image quality in CCTA has not been systematically evaluated yet. In CCTA, the ROI may be positioned in the left atrium (LV) or the ascending aorta (AA). In triple-rule-out-CTA (TRO-CTA), which allows for the evaluation of the pulmonary arteries and the thoracic aorta in addition to the coronary arteries, the ROI is mostly positioned in the left atrium. This choice of ROI positioning is empirical and its effect on the contrast filling of the pulmonary arteries has not been studied systematically. In the current study we evaluated the effect of ROI positioning on image quality of the coronary arteries (left main coronary artery: LM; right coronary artery: RCA) and the pulmonary arteries (right pulmonary artery: RPA; left pulmonary artery: LPA), respectively. Method In the current monocentric retrospective study all patients underwent CCTA by step-and-shoot mode to rule out coronary artery disease at intermediate risk. We compared two groups of patients with ROI in the left atrium or the ascending aorta. Each group contained 96 patients, so overall 192 patients were included (122 male, 70 female, age 21 to 87 years, 61 years on average). To select pairs of patients with similar characteristics, propensity score matching was used. Matching criteria were height, body weight, sex and heart rate. To evaluate the image quality, we used quantitative and qualitative scores. Signal-to-noise ratio (SNR), defined as the quotient of the mean signal intensity and the standard deviation of signal intensity, represented the quantitative score. For generating the qualitative score, overall image quality was assessed independently by two radiologists with ten and six years of experience with CCTA, respectively, using a five point Likert scale. This way, we compared the quality of the depiction of the coronary arteries on the one hand and of the pulmonary arteries on the other hand. For statistical evaluation the Wilcoxon test was used to compare the quantitative and qualitative scores of the two groups. Regarding the qualitative analysis, interrater agreement was evaluated using weighted Cohens kappa. Furthermore the radiation exposure was compared by viewing the dose-length products provided by the scanner and calculating the effective doses from these. Results In terms of the coronary arteries, there was no significant difference between both groups regarding quantitative (SNR AA 14.92 vs. 15.46; p = 0.619 | SNR LM 19.80 vs. 20.30; p = 0.661 | SNR RCA 24.34 vs. 24.30; p = 0.767) or qualitative scores (4.25 vs. 4.29; p = 0.672), respectively. In terms of the pulmonary arteries, we can see significant higher quantitative (SNR RPA 8.70 vs. 5.89; p < 0.001 | SNR LPA 9.06 vs. 6.25; p < 0.001) and qualitative scores (3.97 vs. 2.24; p < 0.001) for bolus tracking positioning in the left atrium than for bolus tracking positioning in the ascending aorta. The calculation of the interrater reliability showed substantial agreement for the analysis of the coronary arteries (κ = 0.654) and almost perfect agreement for the analysis of the pulmonary arteries (κ = 0.846). The radiation exposure was almost identical in both groups of patients (4.13 mSv vs. 4.13 mSv; p = 0.501). Conclusion Bolus tracking positioning in the left atrium or the ascending aorta causes equivalent image quality of the coronary arteries, so that the current mostly preferred position for the exclusively consideration of the coronary arteries in the ascending aorta can be maintained. Positioning in the left atrium causes a significant higher image quality of the pulmonary arteries, therefore it should be used for TRO-CTA. In addition, the study shows that this for TRO-CTA mostly used position in the left atrium does not adversely affect depiction of the coronary arteries, if compared to conventional bolus tracking positioning in the ascending aorta. This implies that despite the improved depiction of the pulmonary arteries and the aorta in TRO-CTA, the depiction of the coronary arteries is not restricted. Consequently these results are a further argument for an extension of the indication for TRO-CTA in place of conventional CCTA in patients with acute thoracic pain.

Chronic kidney disease (CKD) is defined as glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 for 3 months and is characterized by progressive loss of renal function. The second leading cause of CKD is hypertension. More than half of CKD patients also suffer from hypertension. Arteries and arterioles adjust to the fluctuations in the systematic blood pressure through a mechanism called autoregulation. In the kidneys, autoregulation protects the delicate glomeruli capillaries from high blood pressure and occurs through myogenic constriction (MC). MC refers to contraction of arterioles in response to an increase in the blood pressure. Chronically hypertensive individuals and animal models have an enhanced MC, leading to minimal renal injury despite their elevated blood pressure. Experimental and clinical evidence point to a role for the MC in the pathogenesis of the CKD, however, the mechanism through which preglomerular arterial MC contributes to CKD has not been fully elucidated. This thesis showed that augmented MC in chronically hypertensive animal models was due to increased thromboxane A2 prostaglandin that was not released from the endothelium (Chapter 2). Nevertheless, inhibiting MC while also reducing the blood pressure prevented salt-induced renal injury even though the blood pressure was still not normalized compared to the normotensive controls (Chapter 3). The resulting improvement in renal structure and function could be attributed to the reduction in the blood pressure, albumin, and uromodulin (UMOD) excretion (Chapter 3). UMOD is a kidney-specific glycoprotein that, based on a genome-wide association study have the strongest association to CKD (Chapter 3). Comparing two CKD hypertensive animal models further revealed that CKD progression was independent of the blood pressure and strongly associated with UMOD excretion levels (Chapter 4). Collectively, the data discussed in this thesis demonstrates potential therapeutic targets in CKD hypertensive animal models. / Dissertation / Doctor of Philosophy (PhD)

Contexte : La dextro-transposition des gros vaisseaux et la transposition congénitalement corrigée des gros vaisseaux sont des cardiopathies congénitales où le ventricule de morphologie droite est en position sous-aortique (VDs) ou systémique et le ventricule de morphologie gauche est en position sous-pulmonaire donc avec une physiologie biventriculaire. Chez les patients avec un VDs, la capacité maximale à l’effort cardiorespiratoire (CMC) est réduite pour une multitude de facteurs, dont une unique artère coronaire alimentant le VDs en oxygène, une incapacité d’augmenter le volume d’éjection systolique, et/ou une demande accrue en oxygène du VDs hypertrophié menant ultimement à l’ischémie à l’effort. Des études antérieures suggèrent que la CMC est diminuée chez les patients avec un VDs comparativement à celle des individus sains avec un ventricule de morphologie gauche en position sous-aortique (VGs). Aucune étude à ce jour n’a tenté d’apparier des patients avec un VDs à des patients avec un VGs pour les paramètres cliniques tels que la classe fonctionnelle de la NYHA, la fonction systolique similaire du ventricule systémique et la médication. Méthodes : Une étude transversale rétrospective a été réalisée en appariant 24 adultes avec un VDs à 24 adultes avec un VGs pour le sexe, l’âge, l’indice de masse corporelle, la fraction d’éjection du ventricule systémique (normal, légère, modérée, sévère), la classe NYHA (I, II, III) et la prise de diurétiques. La consommation d’oxygène pic (V̇O₂pic), le pourcentage prédit de la V̇O₂pic (% V̇O₂pic) et la pente ventilation/dioxyde de carbone (pente V̇E/V̇CO₂) ont été comparés à un test de Wilcoxon signé-rang. Une sous-analyse a été faite en dichotomisant les groupes selon le critère de Weber selon la CMC (VGs V̇O₂pic > OU ≤ 20 mL/kg/min). Résultats : Un total de 18/24 (75%) patients avaient une classe fonctionnelle NYHA II-III et 23 (96 %) présentaient une dysfonction de leur VDs avec une haute incidence de traitement pour l’insuffisance cardiaque. Contrairement à la littérature antérieure, la V̇O₂pic (VDs: 20.1 ± 4.4 vs. VGs: 20.2 ± 4.8 mL∙ kg-1 ∙ min-1, p=0.966, d=n/a), % V̇O₂pic (63 ± 16 vs 69±17 % p=0.207, d=0.35) et la pente V̇E/V̇CO₂ (29 ± 6 vs 30 ± 6 % p=0.422, d= n/a) ne différaient pas entre les groupes. Après dichotomisation, la V̇O₂pic était plus basse chez les VDs comparativement aux VGs avec une CMC optimale. À l’inverse, la V̇O₂pic était supérieure chez les VDs comparativement aux VGs dont la CMC étaient sous-optimale. Le % V̇O₂pic démontrait un patron similaire, alors que la pente V̇E/V̇CO₂ ne différait pas entre les deux sous-groupes. Conclusion: Pour des patients avec VDs et VGs à circulation biventriculaire appariée pour des caractéristiques cliniques similaire et démontrant un phénotype d’insuffisance cardiaque, aucune différence significative n’était présente au niveau de la CMC. Une analyse plus approfondie suggère la présence de mécanismes physiologiques spécifiques au type de ventricule en position systémique. / Background: Dextro transposition of the great arteries or congenitally corrected transposition of the great arteries are congenital cardiopathies where the morphological right ventricle is in the sub-aortic position (sRV) or systemic and the morphological left ventricle is in the sub-pulmonary position (sRV), thus in bi-ventricular circulation. Cardiorespiratory fitness (CRF) in those patients is reduced by multiple factors including a unique coronary artery, the incapacity to increase stroke volume, and/or an acute oxygen demand caused by the hypertrophied sRV leading ultimately to ischemia. Past studies suggested that CRF is diminished in patients with sRV compared to healthy patients with sLV. No study to date has attempted to match patients with sRV to patients with slV for clinicals parameters as NYHA functional classification, similar function of the systemic ventricle, and medication. Methods: A retrospective cross-sectional study was performed by matching 24 adults with a sRV to 24 adults with a sLV matched for sex, age, body mass index, ejection fraction of the systemic ventricle (normal, mild, moderate, severe), NYHA class (I, II, III), and doses of diuretics. Peak oxygen consumption (V̇O₂peak), percentage predicted of V̇O₂peak (% V̇O₂peak), and ventilation/carbon dioxide production slope (V̇E/V̇CO₂ slope) were compared with a Wilcoxon signed-rank test. A sub-analysis was made by dichotomizing groups according to Weber’s criterion for CRF (sLV V̇O₂peak > OR ≤ 20 mL/kg/min). Results: A total of 18/24 (75%) matched paired were classified as NYHA functional class II-III and 23 (96%) presented a systemic ventricle dysfunction with higher incidence of heart failure treatment. V̇O₂peak (sRV: 20.1 ± 4.4 vs. sLV: 20.2 ± 4.8 mL/kg/min, p=0.966, d=n/a), % V̇O₂peak (63±16 vs 69±17 % p=0.207, d=0.35) and V̇E/V̇CO₂ slope (29±6 vs 30±6 % p=0.422, d= n/a) did not differ between groups. After dichotomization, V̇O₂peak was lower in sRV in those with optimal CRF. Oppositely, V̇O₂peak was greater in sRV in those with suboptimal CRF. The % V̇O₂peak displayed similar patterns, whereas V̇E/V̇CO₂ slope did not differ between sub-groups. 6 Conclusion: No significant differences in CRF were reported when comparing sRV and sLV biventricular physiology after matching the clinical characteristics within a cohort with heart failure phenotype but detailed analyses suggest specific physiological adaptive mechanisms.

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Traumatic brain injury (TBI) is the most frequent cause of death in children and young adults in the United States. Besides emergency neurosurgical procedures, there are few medical treatment options to improve recovery in people who have experienced a TBI. Management of patients who survive TBI is complicated by both central nervous system and peripheral systemic effects. The pathophysiology of systemic inflammation and coagulopathy following TBI has been attributed to trauma-induced endothelial cell dysfunction; however, there is little knowledge of the mechanisms by which trauma might impact the functions of the vascular endothelium at sites remote from the injury. The endothelium lining these small vessels normally produces nitric oxide (NO), arachidonic acid metabolites, and endothelial-dependent hyperpolarizing factors to relax the surrounding vascular smooth muscle. For this research study we investigated the effects of fluid-percussion-induced TBI on endothelial-dependent vasodilatory functions in a remote tissue bed (the mesenteric circulation) 24 hours after injury. We hypothesized that TBI causes changes in the mesenteric artery endothelium that result in a loss of endothelial-dependent vasodilation. We found that vasodilations induced by the muscarinic-receptor agonist, acetylcholine, are attenuated following TBI. While the endothelial-derived hyperpolarizing component of vasodilation was preserved, the NO component was severely impaired. Therefore, we tested whether the loss of NO component was due to a decrease in bioavailablity of the NO synthase (NOS) cofactor BH4, the NOS substrate L-arginine, or to changes in expression/activity of the enzyme arginase, which competes with NOS for L-arginine. We found that supplementation of L-arginine and inhibition of the enzyme arginase rescues endothelial-dependent vasodilations in TBI arteries. This study demonstrates that there are pathological systemic effects outside the point of injury following TBI leading to a dysfunctional endothelial vasodilatory pathway. These data provide insight into the pathophysiology of endothelial dysfunction after trauma and may lead to new potential targets for drug therapy.