Dissertations / Theses on the topic 'Circulation coronaire'

La circulation artérielle coronaire est un système complexe dont les méthodes de mesures invasivespermettent une évaluation en pratique clinique.Matériels et méthodes Nous développons, dans deux revues, les principes et méthodes des différentes techniques invasivesde mesure du flux coronaire en pratique clinique. Puis nous étudions l’impact clinique de l’utilisationde la Fractional Flow Reserve (FFR) dans l’évaluation des sténoses coronaires intermédiaires, lesmoyens pharmacologiques pour mesurer la FFR et sa corrélation avec l’évaluation angiographique enfonction des facteurs de risque cardiovasculaires. Enfin, nous décrivons les principes et méthodesd’une technique de mesure du flux coronaire segmentaire permettant d’obtenir la FFR, le flux et lesrésistances absolues avec un microcathéter de perfusion qui, sur un principe de thermodilutionpermet d’évaluer distinctement la macro et la microcirculation coronaire.Résultats Nous recommandons une valeur seuil de FFR de 0,80 pour guider la revascularisation car le nombred’événements cardiovasculaires et la mortalité sont spontanément supérieurs chez les patients avecune FFR <0,80 comparativement à une FFR ≥0,80 (9,4 vs. 4,8%, P=0,06 et 7,5 vs. 3,2%, P=0,06;respectivement). Nous avons étudié différents agents hyperémiants permettant de mesurer la FFR:l’adénosine (100 μg à 200 μg) permettant d’obtenir une hyperémie maximale, et le produit decontraste permettant d’atteindre 65% de cette hyperémie maximale. La mesure de la FFR avec duproduit de contraste permet de meilleures performances diagnostiques que les indices de reposcomparé à la FFR sous adénosine. Nous avons établi que la corrélation entre la FFR et le degré desténose angiographique est faible et inversement proportionnel au nombre de facteurs de risquecardiovasculaires, particulièrement chez les patients diabétiques. Enfin, nous avons décrit dans troisétudes, le principe de thermodilution coronaire et la méthode de mesures du flux coronaire et desrésistances microvasculaires avec un microcathéter de perfusion intracoronaire spécifique. Nousavons montré que cette technique est précise (R=0,98), qu’elle induit une hyperémie maximale etlocale sans agent hyperémiant et quelle est reproductible chez l’homme (R=0,91).Conclusion La compréhension de la circulation coronaire et l’application chez l’homme des techniques demesure du flux coronaire segmentaire sont essentielles tant en pratique clinique courante qu’enrecherche
Coronary circulation is complex and highly regulated while invasive coronary flow measurements techniques allow the assessment of coronary physiology in clinical practice. Material et methods We describe in two reviews the principles and methods of different invasive coronary flowmeasurements techniques in clinical practice. We study the clinical impact of fractional flow reserve(FFR) in intermediate coronary stenosis, the hyperemic agents and dosage to measure FFR and FFRcorrelation with angiographic indices according to risk factors accumulation. Finally, we describe the principle and method of coronary flow and microvascular resistances measurements with a dedicated infusion microcatheter for coronary thermodilution to obtain assessment of macro and microvascular components of coronary circulation. Results We recommend the FFR cut off value of 0.80 to guide revascularization based on our study showing higher myocardial infarction and death rate in patients treated with medical therapy and FFR<0.80compared to those with FFR>0.80, respectively 9.4 versus 4.8%, P=0.06 and 7,5 versus 3,2%, P=0.06. We studied different hyperemic agents and dosages and showed that intracoronary adenosine at 100μg to 200 μg induce maximal hyperemia while contrast medium induce 65% of maximal hyperemia. Therefore, FFR measurements with contrast medium is feasible and has better accuracy than restindices compared to FFR. We establish the weak correlation between FFR and angiographic indicesand weakens correlation as risk factors accumulates, especially in diabetic patients. Finally, we described in three studies the method of absolute coronary flow and microvascular resistancesmeasurements based on thermodilution principle with a dedicated infusion catheter. We showed anaccurate measurement with this technique (R=0.98), which induces maximal hyperemia without theneed of hyperemic agent with reproducible measurements in humans (R=0,91).Conclusion The use of invasive coronary flow measurements to study the coronary circulation is essential inclinical practice and in research

Ce travail aborde les anomalies de la circulation coronaire mises en evidence chez des patients hypertendus sans autre facteur de risque cardiovasculaire, dont les arteres coronaires sont angiographiquement normales. Ces anomalies, presentes au stade precoce de l'hypertension arterielle, concernent les gros troncs epicardiques et la microcirculation coronaire. La diminution de conductance des arteres coronaires epicardiques (reduction de leur calibre), les perturbations de la vasomotricite des arteres coronaires epicardiques et resistives (etude de la vasodilatation flux-dependante et de la reponse au test au froid), et la diminution de la surface de section maximale de la microcirculation coronaire (diminution de la reserve coronaire) pourraient avoir des effets additifs et limiter de facon significative l'augmentation du debit coronaire necessaire a l'augmentation de la demande en oxygene du myocarde, provoquant des episodes hypoxiques ou anoxiques symptomatiques (angor) ou asymptomatiques (ischemie silencieuse). Le role de l'endothelium est fondamental dans les anomalies de la vasomotricite coronaire. La dysfonction coronaire endotheliale est commune a l'hypertension arterielle et aux autres facteurs de risque cardiovasculaire, et l'endothelium vasculaire a aussi un role cle dans la physiopathologie de l'atherogenese et de la thrombogenese. Les effets du traitement antihypertenseur paraissent prometteurs sur la reserve coronaire (antagonistes des canaux calciques et inhibiteurs de l'enzyme de conversion), et sur la vasomotricite coronaire des arteres epicardiques et resistives (inhibiteurs de l'enzyme de conversion). Des etudes devront etre realisees chez l'hypertendu afin de savoir si certaines classes therapeutiques peuvent diminuer la morbidite/mortalite cardiaque, et par quels mecanismes.

L'insuffisance coronaire et l'infarctus du myocarde sont les premières causes de mortalité et de morbidité dans les pays industrialises. Comme dans la plupart des maladies multifactorielles, de nombreux facteurs de risque prédisposent au développement et à la survenue de la maladie coronaire. Il s'agit des facteurs de risque environnementaux et des facteurs de susceptibilité génétique. Dans le travail présente ici, nous nous sommes focalisés sur des gènes candidats issus du système rénine-angiotensine. Les études développées ont consiste a mesurer le degré d'implication de ce système dans les phénomènes de resténose et de vasoconstriction accrue. Nos résultats suggèrent que l'allèle d du gène de l'enzyme de conversion de l'angiotensine i (eca) constitue un facteur de risque majeur d'occlusion après angioplastie conventionnelle et de resténose après angioplastie avec pose d'endoprothèse coronaire, le stent. Nous avons aussi mis en évidence que l'allèle c du gène du récepteur de l'angiotensine ii de type 1 (at1) est lié à une vasoconstriction coronaire augmentée. Cliniquement, ces résultats sont intéressants car ils permettent d'identifier les patients à haut risque de resténose et/ou de vasoconstriction augmentée dans le but de prévenir les accidents coronaires graves qui pourraient survenir, tels qu'un infarctus post-angioplastie ou un vasospasme. Cependant d'autres études sont nécessaires pour vérifier nos résultats tant au niveau épidemiologique qu'aux niveaux clinique et physiologique.

Les effets et les mécanismes d'action d'une pression partielle artérielle en oxygène (PaO2) élevée sur les résistances coronaires ont été évalués dans un modèle de cœur isolé perfusé au sang. Les conditions expérimentales assuraient un apport en oxygène inchangé (contenu artériel en oxygène et débit coronaire constant) malgré des PaO2 très différentes. Dans ces conditions, une augmentation des résistances coronaires est observée lors de la perfusion d'une PaO2 élevée. Cette action n'implique pas les voies de la cyclooxygénase, du monoxyde d'azote, de la lipooxygénase, ou les radicaux libres. En revanche, un endothélium intact est indispensable pour l'apparition de cette vasoconstriction qui est médiée par la fermeture des canaux potassiques ATP dépendants des vaisseaux coronaires. Dans les mêmes conditions expérimentales, nous avons recherché les intéractions entre une PaO2 élevée et un agoniste α, ou la sérotonine. L'administration d'un bolus de phényléphrine ou de sérotonine amplifie l'action vasoconstrictrice coronaire d'une PaO2 élevée
We investigated the role of the endothelium and of several substances in the coronary vasocontruction induced by a high arterial blood oxygen tension (PaO2)in isolated rabbit hearts perfused with suspension of red blood cells. This suspension prepared by mixing red blood cells and Krebs-henseleit buffer, was oxygenated to obtain control and high PaO2 perfusates. Arterial oxygen contstant in both perfusates by reducing hemoglobin concentration in the high PaO2 perfusate. Coronary blood flow was kept constant so that O2 supply would not vary with the rise in PaO2. Increases in perfusion pressure therefore reflected increased coronary resistance. The high PaO2-induced coronary vasconstriction was not affected by inhibiting cyclooxygenase or lipooxygenase or nitric oxide pathways or free radicals production but was abolished after endothelium damage or by cromakalim. These results demonstrate that 1)the endothelium contributes to teh high PaO2-induced coronary vasocontriction 2)this effect is independent of cyclooxygenase or lipooxygenase products, nitric oxide or free radicals 3)the closure of K(ATP) channels mediates this vasoconstriction. The interaction between high PaO2 and stimulation by the alpha agonist phenylephrine or by serotonin was investigated in the same experimental preparation. After pretreatment with the alpha agonist phenylephrine or by serotonin, perfusion of a high PaO2 solution increased coronary resistance to a value significantly higher than that found without phenylephrine or serotonin

Les mecanismes de passage de l'hypertrophie ventriculaire compensee a l'insuffisance cardiaque ont ete etudies au travers d'un modele experimental d'hypertrophie ventriculaire gauche induite par stenose supravalvulaire de l'aorte ascendante en utilisant les techniques de sonomicrometrie et la mesure des debits myocardiques par la technique des microspheres radioactives chez le chien eveille chroniquement instrumente. Dans ce modele, l'insuffisance cardiaque se caracterise par une alteration de la reserve coronaire localisee aux couches musculaires sous endocardiques et s'accompagne d'ilots de fibrose dans le meme territoire. Une alteration des debits du meme type a ete retrouvee lors d'une perfusion d'isoprenaline; elle s'associe alors a des anomalies systolique et diastolique. Au stade d'hypertrophie compensee, au cours d'un exercice musculaire severe la perfusion des couches musculaires sous endocardiques est alteree. Elle s'associe a une alteration contractile de ces memes zones qui persiste longtemps apres l'arret de l'exercice suggerant une sideration du myocarde. L'alteration contractile parait etre une des premieres alterations du myocarde hypertrophie car elle apparait au debut de l'exercice a un moment ou l'alteration des debits n'est pas observee. Le meme type d'anomalie est retrouvee chez des animaux normaux soumis a 24 heures de surcharge barometrique

Partie I : Objectifs. Ce travail propose une étude anatomique du coeur de porc afin d’élaborer des recommandations pour la réalisation d’une chirurgie cardiaque expérimentale. Matériels et méthodes. 16 porcs ont été étudiés. Le réseau coronaire artériel a été étudié chirurgicalement (n=13) et angiographiquement (n=10). Le réseau veineux coronaire a été analysé par dissections anatomiques (n=13) et injections rétrogrades de bleu de méthylène via le sinus coronaire (n=8). Résultats. Le positionnement intrapéricardique spécifique du coeur de porc, limite l’accès à l’aorte ascendante et à l’oreillette droite et nécessite des précautions particulières pour la réalisation d’une sternotomie et d’une canulation de l’aorte ascendante avec cardioplégie antérograde par la racine de l’aorte. Le réseau coronaire artériel est comparable au réseau humain (réseau droit dominant: 70%). Le sinus coronaire reçoit 4 afférences contre 3 chez l’homme. L’étude de la distribution de surface du réseau veineux nécessite la ligature préalable de la veine azygos gauche et confirme une asymétrie de perfusion au détriment du VD. La paroi antérieure du VD étant drainée par des petites veines cardiaques indépendantes du sinus coronaire. Conclusions. La connaissance des spécificités anatomiques cardiaques du porc a permis d’établir des recommandations pour la réalisation du modèle d’autorétroperfusion myocardique et plus largement de procédures chirurgicales cardiaques expérimentales sécurisées. Partie II : Objectifs. La perfusion rétrograde dans le sinus coronaire est utilisée pour la diffusion d’une solution de cardioplégie. Nous avons développé un modèle porcin d’autorétroperfusion myocardique à coeur battant (SMR) utilisant le réseau veineux coronaire pour assurer l’oxygénation du myocarde ventriculaire gauche. Ce modèle nous a permis d’évaluer les réponses hémodynamiques et cardiaques induites par SMR avant et après occlusion de l’artère IVA. Matériels et Méthodes. Une dérivation entre l’aorte ascendante et le sinus coronaire a été mise en place pour assurer une perfusion rétrograde sélective de la grande veine coronaire en sang oxygéné (SMR). Un groupe Contrôle (n=6) a permis de collecter des données physiologiques de référence et un groupe SMR (n=6) a été spécifiquement dédié à l’évaluation du concept d’autorétroperfusion myocardique après occlusion de l’artère IVA pendant au moins 240 minutes. Le débit cardiaque (CO), la pression maximale intra-VG (Pmax in-LV), le volume éjecté (SV), la fraction d’éjection ventriculaire gauche (FEVG), la durée diastolique (DD), la fréquence cardiaque (HR) et la pression artérielle systémique ont été monitorés en continu durant la période d’autorétroperfusion au moyen d’un cathéter de conductance type Millar® avant et après occlusion de l’IVA. La qualité de la perfusion systémique périphérique a été évaluée par l’analyse de la microcirculation sublinguale. En fin de procédure, les coeurs étaient prélevés pour une analyse histologique. Résultats. L’évaluation échographique de la FEVG était biaisée par la sternotomie alors que celle réalisée par le cathéter de conductance ne l’était pas. Le débit cardiaque après sternotomie a chuté en moyenne de 7.51% (P < 0.05). L’autorétroperfusion avec artère IVA perméable a généré des effets inotropes positifs, caractérisés par une augmentation du CO, du SV, de la Pmax in-LV et de la FEVG (P <0.0001). Après occlusion de l’IVA, l’autorétroperfusion a assuré, durant 240 minutes, une oxygénation myocardique et une compensation hémodynamique garantissant la préservation de la perfusion périphérique. L’analyse histologique a confirmé l’absence d’infarctus myocardique. Conclusions. L’autorétroperfusion myocardique a confirmé des propriétés inotropes positives et protectrices contre l’ischémie ouvrant des perspectives d’applications intéressantes
Part I: Objectives. This work reports an anatomic study of swine heart in order to produce technical recommendations and achieve successful experimental cardiac surgical procedures. Methods. 16 swines were studied. Coronary artery vessels were surgically (n=13) and angiographically (n=10) assessed. Coronary venous vessels were studied by anatomic dissections (n=13) and retrograde injection of methylene blue through the coronary sinus (n=8). Results. Specific pericardial positioning of swine heart dramatically differs from human heart resulting in a limited access to ascending aorta and right atrium, requiring surgical precautions to perform a safe sternotomy and canulation of ascending aorta with an antegrade cardioplegia. Arterial coronary pattern is similar to that of humans (right dominant supply: 70%). Pig coronary sinus receives 4 main branches vs 3 in human sinus. Preliminary ligation of the left azygos vein is required to visualize the surface distribution of methylene blue within the venous vessels, thereby confirming an optimized perfusion of the left ventricle whereas the right ventricle remains poorly perfused. This asymmetry of perfusion results from a specific venous drainage of the right ventricle through small cardiac veins disconnected from coronary sinus. Conclusions. Anatomic knowledge of swine heart validated surgical guidelines for designing the model of self-myocardial retroperfusion and safely performing experimental cardiac surgical procedures. Part II: Background. Retrograde perfusion into the coronary sinus is used to deliver cardioplegia. We developed an in-vivo porcine beating-heart model of self-myocardial retroperfusion (SMR) using the venous route to supply myocardial oxygenation and sought to assess hemodynamic and cardiac responses triggered by SMR before and after a prolonged occlusion of the LAD.Methods. A bypass-line between the ascending aorta and the coronary sinus was made to perform a selective retrograde perfusion of the great cardiac vein with oxygenated blood (SMR). A Control group (n=6) was assigned to collect baseline data, and an SMR group (n=6) was dedicated to undergo SMR with occlusion of LAD for 240 minutes. Cardiac output (CO), maximal pressure in the LV (Pmax in-LV), stroke volume (SV), left ventricular ejection fraction (LVEF), diastolic durations, heart rate, and arterial systemic pressure were evaluated with conductance catheters for the following periods: basal (before SMR), SMR with patent LAD, and SMR with occluded LAD. In order to assess peripheral perfusion, patterns of sublingual microcirculation were analyzed. At the end of the procedures, the hearts were harvested for histology. Results. Echographic LVEF evaluation was affected by sternotomy, but conductance catheter evaluation was not. Following pericardiotomy, CO decreased by 7.51% (P < 0.05). SMR with patent LAD showed inotropic properties with improvements in CO, SV, Pmax in-LV and LVEF (P < 0.0001). Following LAD occlusion, SMR supplied myocardial oxygenation with hemodynamic compensation and preserved the peripheral perfusion. Histology confirmed no signs of infarct. Conclusions. SMR showed capacities to produce inotropic effects and protect against ischemia, opening interesting potential applications

Pour rétablir, ou maintenir, le flux coronarien dans des artères en partie ou totalement obstruées, on implante une endoprothèse qui a la forme d'un petit ressort métallique. Cependant, la pose de ces stents conduit dans 5 à 20% des interventions à une lente réocclusion qui naît en partie de la réponse des cellules pariétales aux efforts hémodynamiques.

Notre étude vise donc à établir numériquement (à l'aide du logiciel Star-CD) et expérimentalement (par PIV et PSV) la topologie de l'écoulement intra stent, mais aussi à quantifier les niveaux de contraintes pariétales au sein du design, en écoulement newtonien et non newtonien. En préambule, une synthèse bibliographique des réponses des cellules constitutives de la paroi artérielle à différents niveaux de contrainte de cisaillement est proposée. La connaissance de ces réponses différenciées des cellules endothéliales et musculaires lisses permet alors de proposer une estimation des régions favorables à la resténose, via le calcul des contraintes de cisaillement qui leurs sont appliquées.

Notre étude paramétrique bidimensionnelle a permis de démontrer la prépondérance de la hauteur des branches sur les risques de resténose. Les résultats tridimensionnels permettent d'estimer les lieux d'une activité mitogénique potentiellement anormale, ainsi que le caractère non newtonien et quasi-stationnaire de l'écoulement intravasculaire au niveau de la paroi artérielle.

This work shows that low doses of carbon monoxyde (CO) corresponding to air pollution impair right ventricle (RV) and right coronary circulation adaptive response in animals preexposed to hypoxic hypoxemia. A complementary study on coronary smooth muscle cell shows that voltage-gated potassium channels contribute to the repolarizing outward membrane currents and they were impaired following hypoxemia and CO exposures. This work provides physiological findings on the cardiac effects of air pollution and increased sensitivity in hypoxic hypoxemic animals. We have used the techniques of cardiovascular functional exploration and electrophysiological assessment of the coronary smooth muscle cell.

The effect of hypoxemia on coronary autoregulation was investigated in nine anesthetized, open-chest dogs. The anterior descending coronary artery (LAD) was cannulated and perfused with normoxic arterial blood and with moderately hypoxic blood (0₂ content = 10 + 1 ml 0₂ /dl). LAD blood flow was measured as perfusion pressure was varied from 140 to 40 mmHg. At perfusion pressures at and above 40 mmHg, hypoxemia significantly increased LAD flow. During normoxia, the autoregulatory closed-loop gain (Gc) was significantly greater than zero at perfusion pressures from 60 to 120 mmHg. During hypoxemia, Gc was greater than zero only at perfusion pressures from 80 to 100 mmHg. During hypoxemia, LAD blood flow increased sufficiently to maintain oxygen delivery and consumption constant, but the range and potency of autoregulation was attenuated.

The coronary circulation first appeared in the chordate lineage in cartilaginous fishes where it perfuses the entire myocardium, just like in birds and mammals but unlike in most teleost fishes. Yet, despite the pivotal position of elasmobranchs in the evolution of the coronary oxygen supply, the functional significance of their coronary circulation has never been investigated. Elasmobranchs are of special interest because of the morphological arrangement of their cardiomyocytes, which has resulted in the majority of the ventricular myocardium having access to oxygen from both a coronary supply and the venous blood returning to the heart. In order to determine the relative contribution of the coronary oxygen supply to cardiovascular function, I measured coronary blood flow (CBF) in the sandbar shark, Carcharhinus plumbeus, and leopard shark, Triakis semifasciata, while manipulating cardiovascular status using pharmacological approaches and in vivo temperature changes, respectively. By exploring inter- and intra-individual variation in cardiovascular variables I show that coronary blood flow is directly related to heart rate in both bradycardic (R²= 0.6, P <0.001) and trachycardic (R²= 0.8, P <0.001) states, as it is in mammalian hearts. I suggest that changes in heart rate are related to changes in coronary vascular resistance in elasmobranchs. As I found that 3-4% of cardiac output is directed towards the myocardium (~0.07% of body mass), a methodology was developed to quantify the degree of the coronary vascularization within the spongy and compact tissues of the shark myocardium. Using this methodology, coronary vascularity and vessel morphology of six species of shark were compared to explore the functional relationships between coronary morphology and physiological phenotypes across species. I further determined that the coronary circulation showed evidence of having evolved in response to different thermal regimes across species. Together the results of this thesis show that the coronary circulation in sharks plays a crucial role in myocardial oxygen delivery to the entire heart, something not previously appreciated, and that habitat temperature plays a role as a selective agent in shaping coronary morphology.
Science, Faculty of
Zoology, Department of
Graduate

This study examines the α-adrenergic constrictor tone varies with intensity of exercise, the effects of coronary α1-adrenergic blockade on left ventricular contractile function and regional myocardial perfusion, and compares the effects of increasing coronary blood flow by removing α1-constrictor tone.

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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Coronary heart disease is one of the leading causes of death worldwide. Although several risk factors are well known; many lesions cannot be explained by these factors alone. The hypothesis of arteries developing lesions due to its morphology, known as geometric risk factors and/or due to hemodynamic forces, has been raised more than thirty years ago. Although investigators have found connection between geometric/hemodynamic variables and lesions, there exists no quantifiable index that helps physicians to predict actual risks. Even when a severe lesion is present, recent studies have found that some patients can develop collateral circulation to provide sufficient blood flow to the myocardium, thus avoiding ischemia. In turn, the gold standard for functional stenosis assessment is an invasive medical exam called Fractional Flow Reserve (FFR). Moreover, these studies are expensive, require highly qualify professionals and involve risks to the patient during intervention. In this context, the goals of the proposed thesis are (i) to fully characterize coronary arterial trees from a geometrical perspective, search for hereditary geometric features and correlations between morphology and disease; (ii) to construct a modeling methodology for the estimation of FFR making use of computational fluid dynamic models built on top of patient-specific medical images of coronary arterial networks. Results for goal (i) include the geometric characterization of a patient sample consisting of siblings. Several studies involving standard and non-traditional geometry-based indexes, in which associations between geometry and lesion presence was found, as well as indications of arterial geometry heritability between siblings. Regarding hemodynamic simulations in the context of FFR, i.e. goal (ii), a novel technique to define patient-specific boundary conditions in 3D models was presented and tested; the impact of image modality, i.e. coronary computed tomography (CCTA) and intravascular ultrasound (IVUS), on hemodynamics variables was assessed for the first time, which helps to better assess the results obtained from the combination of numerical simulations and medical images. A comparison of 3D and 1D CFD simulations for coronary blood flow based purely on FFR is presented. Several computational settings are compared to invasive measurements with results comparable to the state of the art.
A doença coronáriana é uma das principais causas de morte em todo o mundo. Embora vários fatores de risco sejam bem conhecidos; muitas lesões não podem ser explicadas apenas por esses fatores. A hipótese das artérias desenvolverem lesões devido à sua morfologia, conhecida como fatores de risco geométricos e/ou devido a forças hemodinâmicas, foi levantada há mais de trinta anos. Embora tenha sido encontrada uma conexão entre variáveis geométricas/hemodinâmicas e lesões, não existe um índice quantificável que ajude os médicos a prever os riscos reais. Mesmo quando uma lesão grave está presente, estudos recentes descobriram que alguns pacientes podem desenvolver circulação colateral para fornecer fluxo sanguíneo suficiente para o miocárdio, evitando assim a isquemia. Por sua vez, o padrão ouro para avaliar a funcionalidade de uma lesão é o exame médico invasivo chamado Reserva de Fluxo Fracionada (FFR por suas siglas em inglês). Além disso, esses estudos são caros, exigem profissionais altamente qualificados e envolvem riscos para o paciente durante a intervenção. Nesse contexto, os objetivos desta tese são (i) caracterizar completamente as artérias coronárias de uma perspectiva geométrica, buscar características geométricas hereditárias e correlações entre morfologia e doença; (ii) construir uma metodologia de modelagem para a estimativa do FFR, utilizando modelos da dinâmica dos fluidos computacional (CFD por suas siglas em inglês) construídos a partir de imagens médicas de artérias coronárias de pacientes específicos. Resultados para meta (i) incluem a caracterização geométrica de uma amostra de pacientes constituída por pares de irmãos. Vários estudos são realizados envolvendo índices padronizados e não tradicionais baseados na geometria, nos quais foram encontradas associações entre geometria e presença de lesão, bem como indicações de herdabilidade de geometria arterial entre irmãos. Em relação às simulações hemodinâmicas no contexto de FFR, isto é, meta (ii), é apresentada e testada uma nova técnica para definir condições de contorno específicas para cada paciente em modelos 3D; ainda, foi avaliado pela primeira vez o impacto da modalidade de imagem, em particular, tomografia computadorizada coronária (CCTA) e ultrassom intravascular (IVUS), sobre variáveis hemodinâmicas, o que ajuda a avaliar melhor os resultados obtidos pela combinação de simulações numéricas e imagens médicas. Também é apresentada uma comparação de simulações de CFD empregando modelos 3D e 1D do fluxo sanguíneo coronário focado puramente na estimação do FFR. Vários cenários são comparados com medidas invasivas com resultados similares aos encontrados no estado de arte da técnica.

Platelets have been shown to be a main contributor to thrombus formation in stenotic arteries leading to acute coronary syndromes. It is thought that increased activation and adhesion of platelets under variable shear and complex flow conditions contribute to thrombosis. The objective of this work was to evaluate the relationship between asymmetric stenosis hemodynamics and platelet adhesion using in-vitro models developed to properly simulate physiological conditions. In this study, platelet rich plasma was circulated through stenotic and straight coronary artery models. Adhesion results were obtained by post-perfusion fluorescent labelling and imaging of adhered platelets. Analysis of platelet area coverage has shown maximum adhesion occurs in the distal region of the stenosis. Most likely this is due to increased exposure time of platelets to the wall of the recirculation zone following the stenosis and that exposure being directly after a period of high shear stress. This result gives us a better understanding of the importance of both shear and flow conditions in coronary artery thrombosis.

Introduction: The left ventricle, aortic valve and coronary circulation are intimately related. In studying physiology and developing risk stratification models, these systems cannot be considered in isolation. The main aim of the thesis was to improve our understanding of the coupling mechanisms between left ventricle, aortic valve and coronary circulation during exercise in two patient populations: aortic stenosis and coronary microvascular disease. Methods: To characterize the microcirculation and define the forces governing flow, patients with aortic stenosis, coronary microvascular disease and a control cohort underwent simultaneous intra-coronary pressure and Doppler flow assessment, at rest, during exercise and hyperemia. In addition, patients with moderate to severe aortic stenosis, underwent exercise stress echocardiography and predictors of exercise capacity and the development of symptoms were examined. Results: Despite a greater myocardial workload in AS patients compared to controls at rest and during exercise, coronary flow was similar. Hyperemic flow was less in AS compared to controls. At rest coronary flow was higher and microvascular resistance was lower in patients with micorvascular disease compared to controls. With exercise and hyperemia, the relative contribution of accelerating waves increased in controls. The opposite pattern was seen in aortic stenosis and microvascular disease. The cardiac output reserve, defined as the ratio of cardiac output on maximal exercise to the cardiac output at rest was the only independent predictor of exercise capacity in aortic stenosis and the best predictor of the development of symptoms on exercise. Conclusions: Under conditions of stress, patients with aortic stenosis develop a mismatch between myocardial supply and demand. Both patients with aortic stenosis and microvascular disease have a pathophysiological reduction in coronary perfusion efficiency in response to exercise and hyperemia. Cardiac output reserve is an objective measure that integrates the physiological contributions of valve, ventricle, systemic circulation and chronotropic competence and may proof a useful tool in the risk stratification in aortic stenosis.

Introduction The studies in this thesis address the use of laser Doppler flowmetry (LDF) and pulse photoplethysmography (PPG) in assessing the endothelial function in the dermal microcirculation in people with coronary artery disease (CAD). Measurements included assessment of endothelial function, lipid profile, inflammatory markers and asymmetric dimethylarginine (ADMA). Methods Forty-eight people with coronary artery disease (24 with stable angina and 24 people with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) were compared with 25 healthy controls. Endothelial function was assessed using LDF and PPG. Circulating markers of inflammation, serum lipids and ADMA were measured by standard laboratory methods. People with CAD were treated with statins. Ten healthy controls had repeat measurements by LDF to assess reproducibility of the measurements and 34 people with CAD had repeat LDF measurements three months after PCI. Results 1. The people with CAD and healthy controls were matched for age and gender. The body mass index (BMI) and systolic blood pressure was significantly higher in people with CAD. The serum total cholesterol, low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein cholesterol (HDL cholesterol) and apolipoprotein A 1 were significantly lower in people with CAD. Serum highly sensitive CRP (hsCRP), triglyceride and ADMA levels were significantly higher in people with CAD. People with ACS had higher BMI, hsCRP and lower apolipoprotein A 1 levels compared to people with stable angina. 2. Perfusion changes measured by LDF in response to acetylcholine (ACh) iontophoresis, local heating and reactive hyperaemia had good reproducibility with coefficients of variation (CV) less than 25%. The CV for perfusion changes in response to heating was better than the changes in response to ACh iontophoresis and reactive hyperaemia. 3. Endothelial function measured by LDF and PPG was significantly impaired in people with CAD (p