Thèses sur le sujet « Stiffness arteriosa »

Le malattie infiammatorie croniche intestinali (IBD) sono associate ad un aumentato rischio cardiovascolare non completamente spiegabile con la prevalenza dei fattori di rischio cardiovascolare tradizionali. L'infiammazione e l'aumento della rigidità arteriosa ad essa correlata potrebbero avere un ruolo importante nella valutazione del rischio cardiovascolare di questi soggetti. In questa tesi ho studiato la correlazione tra infiammazione e rigidità arteriosa nelle IBD. Per la prima volta ho riportato che i soggetti con IBD hanno un'aumentata rigidità arteriosa che può essere normalizzata dall'uso di farmaci anti TNF-alfa.

L’introduzione dalla terapia antiretrovirale (ART ) ha determinato una notevole riduzione della morbidità e mortalità nei pazienti HIV positivi. È però stato evidenziato un aumento degli eventi cardiovascolari in questi soggetti. Scopo del nostro studio è stato valutare l’effetto su parametri arteriosi di due differenti protocolli di terapia antiretrovirale su soggetti HIV positivi naive ovvero mai sottoposti precedentemente a terapia antiretrovirale. Abbiamo studiato 40 pazienti HIV positivi naive prima (tempo 0) e dopo 6 mesi (tempo 1) durante i quali i pazienti, suddivisi in 2 gruppi, sono stati sottoposti a 2 differenti protocolli di terapia antiretrovirale. I pazienti del gruppo A (19 soggetti) sono stati sottoposti a terapia con 2 Inibitori nucleosidici della trascrittasi inversa -NRTI+ 1 Inibitori non nucleosidici della trascrittasi inversa -NNRTI. I pazienti del gruppo B (21 soggetti) ) sono stati invece sottoposti a terapia con 2 Inibitori nucleosidici della trascrittasi inversa -NRTI+ 1 Inibitore delle Proteasi-PI. Utilizzando la metodica di echotracking con Esaote Gold 60® abbiamo analizzato la distensibilità carotidea (Dist), lo spessore miointimale e la funzione endoteliale mediante la Flow Mediated Dilation (FMD); grazie al Complior System® abbiamo invece valutato la Pulse Wave Velocity (PWV). I due gruppi (A e B) erano sovrapponibili per età (38.2 ± 9.4 vs 40.2± 9.1 anni); sesso (femmine 15.7% vs 19%) , pressione arteriosa, BMI, conta dei CD4 e titolo HIV-RNA, glicemia e profilo lipidico. Alla prima valutazione (tempo 0) i parametri da noi analizzati sulla struttura e funzionalità arteriosa (Distensibilità carotidea, spessore miointimale, PWV e FMD) presentavano valori di normalità in entrambi i gruppi. Alla seconda valutazione (tempo1) come ci si aspettava abbiamo osservato un incremento dei CD4 e una diminuzione del titolo HIV-RNA; abbiamo inoltre osservato un incremento dei valori di colesterolemia totale, LDL e HDL in entrambi i gruppi mentre i parametri arteriosi non hanno subito modificazioni statisticamente significative sia per quanto riguarda i 2 differenti gruppi sia per quanto concerne le misurazioni effettuate all’interno dello stesso gruppo prima di iniziare la terapia antiretrovirale e dopo 6 mesi di terapia. Durante il periodo osservazionale di 6 mesi i due protocolli antiretrovirali messi a confronto e in particolare l’NNRTI e PI non sembrano modificare i parametri utilizzati per la valutazione della struttura e la funzionalità arteriosa. È possibile che occorra un periodo più lungo perché si determinino tali alterazioni.

The studies in this thesis assess the ventilatory and vascular effects of short-term awake isocapnic hypoxia in healthy subjects and those with obstructive sleep apnoea (OSA). The particular focus of this thesis is the impact of the hypoxic stimulus on indices of arterial stiffness, in particular the augmentation index (AIx) and time to reflection (Tr). The role of nitric oxide in this response in healthy subjects is also examined.

Large artery stiffness is predictive of adverse cardiovascular events and all cause mortality. Artery structure and function are determinants of artery stiffness. This thesis presents a series of in-vivo experimental studies of effect of structural and functional changes on large artery stiffness. Improved analysis methods were developed for measurement of arterial stiffness indexes, Pulse Wave Velocity (PWV) and pressure wave re ection. These were applied in studies of acute in ammation, active and passive changes in systemic pressures, aortic elastic laminae defects, and aortic calcification in rats using a novel, high fidelity, dual pressure sensing technique of measuring aortic rat PWV. Findings indicated that acute in ammation does not increase large artery stiffness, and that localised effects altering arterial structure do not manifest in in-vivo changes in large artery stiffness. The functional component of stiffness was investigated using graded systemic infusion of vasoconstrictor agents (angiotensin-II, noradrenaline, and Endothelin-1 (ET-1)) in the in-vivo ovine iliac artery. There was a markedly greater dose dependency of pressure independent change in PWV (angiotensin-II) compared to direct endothelial effects (ET-1), although blocking of ET-1 receptors produced marked changes in iliac blood ow. A similar experiment in the human iliac artery found that the B-antagonist and nitric oxide (NO) donor, x Structural and functional effects on large artery stiffness nebivolol, potentially causes a decrease in regional functional stiffness. An additional study in human subjects directly measured the decrease in forearm arterial stiffness during reactive hyperaemia following different periods of ischaemia. The findings precluded the use of this method in measuring brachial artery structural stiffness with maximal smooth muscle relaxation. Increasing periods of ischaemia had a bi-phasic relationship with changes in arterial stiffness, the first phase linked to endogenous nitric oxide release. This finding is of importance in the clinical quantification of endothelial dysfunction. These findings in basic research of arterial haemodynamics provide new quantitative contributions to the in-vivo experimental investigation of the aetiology of large artery stiffness related to structure and function of endothelial and medial wall properties. This can lead to potential clinical applications and techniques for assessment of cardiovascular risk.

Increased arterial stiffness is a predictor of cardiovascular events and mortality across a diverse range of populations. Although gross-mechanical stiffness can be measured in vivo, in order to understand the pathological mechanisms it will be necessary to identify which local micro-structural remodelling events are the prime drivers of altered macro-mechanical function. However, characterisation of arterial structure by conventional histological approaches: i) commonly induces artefacts as a consequence of the sectioning process, ii) provides no insight into the three dimensional structure of the tissue and iii) is performed on unpressurised tissue. This project has set out to address these limitations by developing new micro computed x-ray tomography (micro-CT) methodologies which are capable of visualising the three dimensional structure of rat arteries. This new methodology was then been applied in combination with gross-and micro-mechanical testing and atomic force microscopy imaging to characterise the effects of both intra-luminal pressure and age on arterial structure and function. From these investigations it was clear that micro-CT could readily distinguish discrete tissue sub-structures in paraffin embedded tissues, including skin and arteries and that this imaging approach was compatible with complimentary histological and immunohistochemical analyses. Characterisation of the structure and mechanical function of carotid arteries in aged rats demonstrated localised stiffening in the adventitial layer and a change in the molecular structure of adventitial collagen. The effects of intra-luminal pressure on structure using micro-CT revealed changes in artery cross-sectional area, which suggest the artery wall may be compressible. Investigations into the effects of pressure on the molecular structure of adventitial collagen revealed an increase in periodicity at mean pressure. These findings together demonstrate that the adventitial layer has an important role in the development of arterial stiffness. Micro-CT can reveal novel information that improves our understating of artery structure and how artery structure changes during ageing.

The present series of in vivo experiments in healthy subjects, were performed to investigate wall stiffness in peripheral vessels and how this modality adapts to iterative increments or sustained reductions in local intravascular pressures. Vascular stiffness was measured as changes in arterial and venous diameters, and in arterial flow, during graded increments in distending pressures in the vasculature of an arm or a lower leg. In addition, effects of intravascular pressure elevation on flow characteristics in veins, and on limb pain were elucidated. Arteries and veins were stiffer (i.e. pressure distension was less) in the lower leg than in the arm. The pressure-induced increase in arterial flow was substantially greater in the arm than in the lower leg, indicating a greater stiffness in the arterioles of the lower leg. Prolonged reduction of intravascular pressures in the lower body, induced by 5 wks of sustained horizontal bedrest (BR), decreased stiffness in the leg vasculature. BR increased pressure distension in the tibial artery threefold and in the tibial vein by 86 %. The pressure-induced increase in tibial artery flow was greater post bedrest, indicating reduced stiffness in the arterioles of the lower leg. Intermittent increases of intravascular pressures in one arm (pressure training; PT) during a 5-wk period decreased vascular stiffness. Pressure distension and pressure-induced flow in the brachial artery were reduced by about 50 % by PT. PT reduced pressure distension in arm veins by 30 to 50 %. High intravascular pressures changed venous flow to arterial-like pulsatile patterns, reflecting propagation of pulse waves from the arteries to the veins either via the capillary network or through arteriovenous anastomoses. High vascular pressures induced pain, which was aggravated by BR and attenuated by PT; the results suggest that the pain was predominantly caused by vascular overdistension. In conclusion, vascular wall stiffness constitutes a plastic modality that adapts to meet demands imposed by a change in the prevailing local intravascular pressure. That increased intravascular pressure leads to increased arteriolar wall stiffness supports the notion that local pressure load may serve as a “prime mover” in the development of vascular changes in hypertension.
medicine doktorsexamen QC 20101109

Introduction – Objectives. The cardiovascular system is in direct and constant interaction with its environment. Exposure to various environmental parameters, such as low temperature, air pollution and tobacco smoke, has been strongly associated with serious or even fatal cardiovascular outcomes. Arterial stiffening and greater wave reflection are age-related vascular modifications that lead to an increased risk of cardiovascular events. The aim of this work was to explore the relationship between selected environmental factors and arterial elastic properties in an effort to elucidate the underlying mechanisms that link these factors to increased cardiovascular mortality.

Study 1: Effects of cold exposure on central and peripheral vascular tone. Our first study explored the effects of cold exposure on aortic stiffness and peripheral microvascular tone. We observed that cold exposure, in addition to its chronotropic effects, provoked an increase in aortic stiffness, as assessed by aortic pulse wave velocity, as well as significant vasoconstriction of peripheral arterioles in the microcirculation. Moreover, we explored the magnitude of this effect in a different population (Black subjects of African origin), which is traditionally characterized by exaggerated reactions to adrenergic stimuli. We noted that the vascular reactions, in terms of both aortic stiffness and microvascular vasoconstriction, were more profound in Black Africans than in age-matched Caucasian-Whites. These results argue for a direct effect of cold exposure on arterial stiffness and peripheral vascular tone, probably through activation of the orthosympathetic system.

Study 2: Exposure to ambient particulate matter and arterial stiffness. We explored the effects of acute exposure to outdoor particulate matter on aortic stiffness and aortic wave reflection. We studied the relationship between central hemodynamic parameters and ambient concentration of particulate matter in a population of patients who attended the Hypertension Clinics of Athens University. After statistical correction for a number of potential confounders, we did not observe an association between ambient concentrations of particulate matter and aortic stiffness. However, in men, particulate matter concentration was related to the amplitude of the reflected wave reaching the aorta from the periphery. These results suggest a direct acute interaction between particulate matter concentration and vascular tone, leading to an enhanced arterial wave reflection.

Study 3: The role of nicotine on the vascular effects of environmental tobacco smoke. Environmental tobacco smoke is considered as the most important source of particulate matter in the indoor environment. We recently demonstrated that exposure to tobacco smoke augmented wave reflection, an effect that was not seen after equivalent exposure to the smoke of non-tobacco, herbal cigarettes. We also noticed that the increased wave reflection was proportional to the plasma concentrations of nicotine. However, a direct causal effect between nicotine, arterial wave reflection and aortic stiffness has never been clearly demonstrated. We observed that increasing nicotine plasma concentration to levels comparable to those seen after extensive exposure to environmental tobacco smoke, provoked an increase in both aortic stiffness and arterial wave reflection after correction for heart rate and blood pressure changes. These results confirm the significant participation of nicotine in the vascular effects of passive smoking.

Conclusions. Globally, our results reveal the deleterious effects of cold, particulate matter exposure, and nicotinic stimulation on arterial stiffness, peripheral microcirculation and aortic wave reflection. The hemodynamic modifications associated with these effects may at least partially explain the causal relation between cold exposure, ambient air pollution and cardiovascular mortality.

Introduction-Objectifs. Le système cardiovasculaire est en relation directe et constante avec l’environnement. L’exposition au froid, la pollution atmosphérique et le tabagisme passif sont associés à des événements cardiovasculaires aigus graves et même fatals. La rigidification des artères et l’intensification de la réflexion de l’onde de pouls au niveau de l’aorte accompagnent le vieillissement et prédisent un risque cardiovasculaire accru. Nous avons testés l’hypothèse que les effets cardiovasculaires délétères des facteurs environnementaux comportent une altération des propriétés élastiques artérielles. Ceci pourrait être un des mécanismes physiopathologiques qui lie la mortalité cardiovasculaire aux variables environnementales.

Étude 1 :Exposition au froid ;effets centraux et périphériques. Notre première étude portait sur l’effet de l’exposition au froid sur la rigidité aortique et le tonus vasculaire des artérioles périphériques. Nous avons démontré que l’exposition au froid, hormis ses effets chronotropes, provoquait une augmentation de la rigidité artérielle – mesuré par la vitesse de l’onde de pouls au niveau de l’aorte - ainsi qu’une vasoconstriction importante au niveau des artérioles de la microcirculation. Nous avons ensuite déterminé l’amplitude de cet effet dans une autre population (sujets Africains-Noirs) qui se caractérise par des réactions plus prononcées aux différentes stimulations adrénergiques. Nous avons observé que les réactions vasculaires, tant au niveau de la rigidité aortique qu’au niveau de la microcirculation, étaient plus marquées chez les Africains-Noirs que chez les Caucasiens. Ces résultats révèlent un effet délétère de l’exposition au froid sur la rigidité aortique et le tonus vasculaire des artères périphériques, probablement via une activation du système orthosympathique.

Étude 2 :Exposition aux microparticules atmosphériques et rigidité artérielle. Nous avons ensuite investigué les effets de la pollution atmosphérique sur la rigidité artérielle et la réflexion de l’onde de pouls vers l’aorte. Nous avons étudié la relation entre les paramètres hémodynamiques centraux et la concentration atmosphérique de microparticules dans une population de patients qui ont consulté la Clinique Universitaire d’Hypertension Artérielle d’Athènes. Après correction statistique pour les facteurs confondants, nous n’avons pas observé de corrélation entre la rigidité artérielle et le taux de microparticules atmosphériques dans l’ensemble de la population investiguée. Par contre, si on restreint l’analyse aux résultats obtenus chez les sujets masculins, on s’aperçoit que la concentration atmosphérique de microparticules était associée de façon significative avec l’amplitude de l’onde réfléchie par la périphérie vers l’aorte et la pression pulsée aortique. Ces résultants suggèrent un effet direct des microparticules au niveau de la microcirculation. L’augmentation de l’amplitude de l’onde réfléchie consécutive à une vasoconstriction périphérique, modifie vraisemblablement les pressions au niveau de l’aorte chez le sujet masculin lors de pics de pollution.

Etude 3 :Le rôle de la nicotine dans les effets vasculaires du tabagisme passif. Le tabagisme passif est considéré comme la source la plus importante d’émission de microparticules au niveau domestique. Cependant, la composition chimique des particules semble jouer un rôle essentiel sur les ondes de réflexion. Nous avons démontré récemment que l’exposition passive à la fumée des cigarettes du tabac augmente l’intensité de la réflexion de l’onde de pouls. Ceci n’a pas été observé avec l’exposition à la fumée des cigarettes non tabagiques, en dépit d’une concentration ambiante tout à fait comparable de microparticules. Par ailleurs, nous avons observé que l’augmentation de l’incidence de l’onde de pouls au niveau de l’aorte était fortement associée à la concentration plasmatique de la nicotine. Un lien causal entre la nicotine, réflexion de l’onde de pouls et rigidité artérielle n’avait jamais clairement été établi. Nous avons testé cette hypothèse en administrant la nicotine pure chez des sujets sains. Nous avons observé que l’augmentation des taux plasmatiques de la nicotine à des valeurs comparables à celles qui surviennent après une exposition intensive au tabagisme passif, intensifiait la réflexion de l’onde de pouls et augmentait la rigidité artérielle. La correction statistique pour l’augmentation de la fréquence cardiaque et l’augmentation de la pression artérielle en réponse à la nicotine ne modifiait pas ces conclusions. Nos résultats démontrent ainsi les effets cardiovasculaires importants de faibles concentrations de nicotine, similaires à ceux qui sont atteints en cas d’exposition à un tabagisme passif.

Conclusions. Nos résultats révèlent les effets néfastes de l’exposition au froid et aux microparticules atmosphériques sur la rigidité artérielle, la microcirculation périphérique et la réflexion de l’onde de pouls. Nous avons pu également démontrer le rôle de la stimulation nicotinique dans les effets vasculaires aigus du tabagisme passif, comme en témoigne l’augmentation de la réflexion de l’onde de pouls au niveau aortique. Ces modifications hémodynamiques favorisent l’ischémie myocardique, et constituent un des mécanismes par lesquels l’exposition au froid et à la pollution atmosphérique favorisent la pathologie cardiovasculaire.

Doctorat en Sciences médicales
info:eu-repo/semantics/nonPublished

Les antiangiogéniques (AAD) représentent une classe relativement récente d’anticancéreux indiqués dans un nombre croissant de cancers solides avancés. Ces traitements inhibent la voie du VEGF en amont avec le bevacizumab, un anticorps monoclonal dirigé contre le VEGF et en aval avec les inhibiteurs des tyrosines kinases des récepteurs impliqués dans cette voie de signalisation (sorafenib et sunitinib). Les AAD s’accompagnent d’effets secondaires dont le plus fréquent est l’hypertension artérielle. Ma thèse a pour objectif de mieux comprendre la physiopathologie de l’hypertension artérielle iatrogène induite par les AAD, notamment en mesurant l’effet des AAD sur les grosses artères. Le deuxième objectif est de déterminer des marqueurs précoces d’efficacité et d’optimisation de ces traitements, notamment avec un suivi thérapeutique pharmacologique (STP). Pour remplir ces objectifs nous avons mis en place une étude clinique prospective, observationnelle monocentrique dans laquelle nous avons suivi l’évolution de paramètres artériels au cours du traitement AAD avec des techniques non-invasives chez des patients atteints d’un cancer. Dans un premier travail nous avons montré qu’il y avait une augmentation précoce et cliniquement significative de la pression brachiale et centrale, de la rigidité artérielle et du diamètre carotidien sous AAD et que ces modifications étaient en partie indépendantes de la pression artérielle. Nous avons également montré que la présence d’ondes de réflexion amples et d’une rigidité aortique basse de base avant l’introduction des AAD prédisaient une augmentation de pression artérielle systolique (PAS) à un stade précoce d’exposition (coefficients de régression : 0.37[0.04-0.70] et -1.27[-2.43 ; -0.11], p<0.05 respectivement) alors qu’après une exposition chronique aux AAD, seule une rigidité artérielle basse de base prédisait une augmentation de la PAS (-2.46 [-4.02 ; -0.90], p<0.01). L’atteinte des grosses artères est positivement associée à l’évolution carcinologique. En effet une augmentation précoce de la rigidité aortique et carotidienne sous AAD étaient associées à un haut risque de progression (HR : 1.24 [1.01 ; 1.51], p=0.042 et 1.34 [1.03-1.73], p=0.027 respectivement). Dans la deuxième partie, nous avons montré à l’aide d’un modèle pharmacocinétique de population, que l’atteinte artérielle observée lors de la prise d’AAD était due à un effet pharmacologique des AAD sur les grosses artères indépendamment de l’augmentation de pression induite par les AAD. L’augmentation de rigidité artérielle était proportionnelle à la concentration plasmatique d’AAD et à l’augmentation de la pression artérielle (coefficient de corrélation standardisé : 0.37 et 0.35, p<0.01, respectivement), expliquant respectivement 13% et 11% de la variance. Nous avons également montré que la progression et la mortalité liées au cancer étaient moindre chez les patients les plus exposés aux AAD (HR : 0.60 [0.38 ; 0.97], p=0.035 et HR=0.38 [0.19-0.79], P=0.01 respectivement) et enfin, nous avons pu déterminer une concentration sérique cible qui permettra aux cliniciens d’avoir un objectif à atteindre pour optimiser l’efficacité des AAD. En conclusion, nous avons pu démontrer l’existence d’une atteinte précoce des grosses artères se traduisant par une augmentation de la rigidité artérielle et un remodelage carotidien sous traitement AAD. Cette atteinte artérielle est directement liée à un effet pharmacologique des AAD de manière indépendante de l’augmentation de pression induite par ces traitements. Nous avons montré que les altérations de la paroi artérielle ainsi que le suivi thérapeutique pharmacologique prédisaient le pronostic carcinologique. Le suivi des propriétés artérielles combinée au STP des AAD pourraient optimiser les chances d’efficacité de ces traitements
Antiangiogenic drugs (AAD) are a relatively new class of anti-cancer therapy indicated in an increasing number of advanced solid tumors. By inhibiting the VEGF pathway, upstream with an anti-VEGF monoclonal antibody, bévacizumab, and downstream with tyrosine kinase inhibitors of receptors involved in this signaling pathway (sorafenib and sunitinib), AAD induce arterial hypertension which is the most common side effect. The principal objective of my thesis is to improve the understanding of the pathophysiology of hypertension induced by AAD, by determining the effect of AAD on large arteries. The second objective is to determine early marker of efficacy and optimization of AAD, by the use of therapeutic drug monitoring. To fulfill those objectives, we set up a clinical prospective, observational, single center study in which we followed the time-course of several arterial parameters after AAD by the use of non-invasive techniques in patients with metastatic solid tumors. In a first work we showed that brachial and central blood pressure, arterial stiffness and carotid diameter significantly increased after AAD, partly independently of blood pressure changes. We also showed that high reflection waves and low aortic stiffness at baseline (i.e. before AAD initiation) predicted early systolic blood pressure (SBP) increase (regression coefficients: 0.37[0.04; 0.70] and -1.27[-2.43; -0.11], P<0.05 respectively) while only low aortic stiffness predicted SBP increase after chronic AAD exposure (-2.46 [-4.02 ; -0.90], P<0.01). Large arteries damage under AAD is positively associated with cancer progression. Indeed, early increase of aortic and carotid stiffness after AAD were associated with a higher risk of cancer progression (HR: 1.24 [1.01; 1.51], P=0.042 and 1.34 [1.03; 1.73], P=0.027 respectively). In a second part, using a pharmacokinetic model of population, we showed that large arteries damage observed after AAD was partly due to a pharmacological effect of AAD on large arteries independently of blood pressure increase. Arterial stiffness increase was proportional to AAD blood concentration and blood pressure increase (standardized correlation coefficients: 0.37 and 0.35, P<0.01, respectively), explaining 13% and 11% of the variance respectively. We also showed that progression and mortality related to cancer were lower in patients high AAD blood concentrations (HR: 0.60 [0.38; 0.97], P=0.035 and HR=0.38 [0.19; 0.79], P=0.01 respectively). And finally, we determined a target AAD blood concentration which will allow the clinicians to have an objective to reach in order to optimize the efficacy of AAD. In conclusion, we were able to demonstrate the existence of large arteries damage translated by large arteries stiffening and a remodeling of carotid artery after AAD. This arterial damage is directly related to a pharmacological effect of AAD independently of blood pressure changes induced by these treatments. We showed that infringement of the arterial wall and the therapeutic drug monitoring predicted tumor prognosis. Thus, the monitoring of arterial properties monitoring and the therapeutic drug monitoring might optimize the chances of efficiency of AAD

Introdução: As células do músculo liso vascular (CMLV) são quiescentes nos vasos adultos, com baixa capacidade de migração e de secreção de matriz extracelular, caracterizando fenótipo contrátil. Evidências apontam para a heterogeneidade fenotípica das CMLV ao longo da árvore arterial: há distribuição heterogênea de doenças e de resposta a determinadas drogas nos diferentes vasos, além de variabilidade de expressão dos genes de proteínas contráteis de músculo liso entre eles. O papel das CMLV, em fase adulta, é classicamente descrito como restrito à regulação do tônus de pequenos vasos, sendo insignificante a contribuição da mecânica das CMLV para a complacência das artérias elásticas. Existe a hipótese de que a viscoelasticidade das CMLV contribua para a mecânica final das artérias, sendo o enrijecimento dessas células associado à rigidez arterial. Objetivo: Estudar a variabilidade das propriedades mecânicas e de expressão proteica das CMLV, ao longo da árvore arterial, buscando identificar moduladores regionais para esse fenótipo. Avaliar se situações clínicas sabidamente associadas à rigidez arterial (envelhecimento, sexo feminino pós-menopausa, ancestralidade genética africana, diabetes mellitus e tabagismo) cursam com enrijecimento de CMLV. Métodos: 1) Estudou-se a composição e a organização da camada média de diferentes artérias. As CMLV desses vasos foram avaliadas quanto à viscoelasticidade de citoplasma (G), por meio do ensaio de Citometria Magnético Ótica de Oscilação e, quanto à expressão proteica global, usando cromatografia multidimensional e espectrometria de massas em tandem de alta resolução (Proteômica Shotgun). Os dados mecânicos obtidos foram correlacionados com as características da matriz extracelular (MEC) dos vasos de origem (porcentagem de elastina e quantidade de MEC). Em paralelo, foi realizado experimento de estiramento cíclico (10%/1Hz) das CMLV das diferentes artérias por 24 e 48h, seguido pela mensuração de rigidez de citoplasma. 2) Foram isoladas as CMLV de fragmentos de artéria mamária de 80 pacientes submetidos à cirurgia de revascularização do miocárdio, células essas que foram avaliadas quanto à viscoelasticidade de citoplasma (G, G\' e G\'\'). Elaborou-se modelo estatístico para avaliar se as variáveis clínicas idade, sexo feminino, ancestralidade africana, tabagismo e diabetes mellitus estavam associadas a alterações de mecânica celular. Resultados: 1) A viscoelasticidade das CMLV variou significativamente entre as artérias. As CMLV provenientes de artérias distais (artérias femoral e renal) mostraram-se significativamente mais rígidas que as CMLV de aorta torácica (p < 0,001). Identificou-se correlação negativa entre rigidez de CMLV e quantidade de MEC / elastina na camada média vascular. O regime de estiramento cíclico por 48h reduziu globalmente a rigidez das CMLV. As CMLV provenientes da aorta torácica expressaram maior quantidade de proteínas relacionadas com a estrutura e a organização do citoesqueleto em relação às CMLV da artéria femoral. 2) Constatou-se variabilidade interindividual de viscoelasticidade de CMLV e associação entre tabagismo e sexo feminino com enrijecimento de CMLV. Conclusões: As CMLV são heterogêneas quanto às propriedades mecânicas, à organização do citoesqueleto e à expressão proteica ao longo da árvore arterial, reforçando o conceito de plasticidade fenotípica das CMLV. A mecânica das CMLV é modulada pelas características da MEC e pela tensão circunferencial cíclica aplicada às paredes vasculares pelo fluxo sanguíneo. Mulheres pós-menopausa e tabagistas exibem enrijecimento de CMLV, sendo esse fato um provável contribuinte para a rigidez arterial associada a essas condições e um possível alvo terapêutico a ser avaliado futuramente
Rational: Vascular smooth muscle cells (VSMC) lose their ability to migrate and secrete extracellular matrix (ECM) with the end of vascular development, condition known as contractile phenotype and reversible in the presence of vascular injury. There is evidence of heterogeneity of VSMC phenotype along arterial tree, as the distribution of diseases (atherosclerosis) and the response to drugs vary between different vessels, as well as the expression of smooth muscle-contractile protein genes. The role played by VSMC mechanics on determining large arteries\' compliance was always considered irrelevant. It has been hypothesized that the VSMC mechanical properties are important for vascular mechanics, especially in the pathological scenario, where VSMC stiffening may be associated with arterial rigidity. Goals: Study the variation of VSMC mechanics and protein expression along arterial tree, identifying regional modulators of this phenotype. Evaluate if clinical situations associated with arterial rigidity (ageing, post-menopausal women, African ancestry, diabetes mellitus and smoking) concur with VSMC stiffening. Methods: 1) Different arteries were studied in terms of composition and organization of their media layer. VSMC isolated from these arteries were evaluated regarding cytoplasm viscoelasticity, measured using Optical Magnetic Twisting Cytometry Assay (OMTC), and protein expression, using two-dimensional liquid chromatography and tandem mass spectrometry (Shotgun Proteomics). Mechanical data were correlated with ECM characteristics (percentage of elastin and ECM amount) of the vessels of origin. In parallel, VSMC of different arteries were subjected to cyclic stretching (10%/1Hz) during 24 and 48h, followed by the measurement of their cytoplasm rigidity. 2) VSMC were isolated from fragments of mammary artery of 80 patients subjected to coronary bypass surgery and evaluated regarding their viscoelasticity (G, G\' e G\'\'). A statistic model was elaborated to address if the clinical variables age, female sex, African ancestry, smoking and diabetes mellitus were associated with changes of VSMC mechanics. Results: 1) VSMC viscoelasticity varied significantly amongst the studied arteries. VSMC from heart-distant arteries (femoral and renal arteries) were stiffer than VSMC from thoracic aorta (p < 0,001). There was a negative correlation between VSMC rigidity and the amount of ECM / percentage of elastin within the media layer. 48h-cyclic stretching was associated with a global reduction of VSMC rigidity. VSMC of thoracic aorta expressed significantly more proteins associated with cytoskeleton structure and organization than VSMC of femoral artery. 2) There was a significant inter-individual variation of VSMC viscoelasticity. Smoking and female sex were associated with VSMC stiffening. Conclusion: VSMC mechanics, cytoskeleton organization and protein expression are heterogeneous along arterial tree. VSMC mechanical properties are modulated by ECM characteristics and by regional mechanical forces. This reinforces the concept of phenotypic heterogeneity of VSMC. Post-menopausal women and smokers exhibit stiffer VSMC, representing an important factor for the understanding of the arterial rigidity associated with these conditions and also a possible future therapeutic target

As propriedades funcionais e estruturais das grandes artérias tem sido foco de atenção nos últimos anos para o melhor entendimento das alterações fisiopatológicas associadas à hipertensão arterial e ao envelhecimento. Muitas destas alterações como a rigidez arterial, tem sido consideradas marcadores independentes de risco cardiovascular. A avaliação destas propriedades não foi estudada em hipertensos mais graves, onde o risco de complicações é maior. O objetivo do estudo foi avaliar, em pacientes com hipertensão estágio 3, as alterações vasculares estruturais e funcionais em grandes artérias, seus principais determinantes e suas correlações com lesões de órgãos-alvo. Foram avaliados 48 pacientes (idade média 53,6 ± 8 anos; 75% brancos; 71% mulheres), com hipertensão arterial estágio 3, recebendo o mesmo tratamento anti-hipertensivo por um mês. A avaliação dos parâmetros carotídeos (diâmetro, espessura e distensão) foi realizada pelo ultrassom de radiofrequência e a rigidez arterial pela medida da velocidade de onda de pulso (VOP) e pelo Índice Ambulatorial de Rigidez Arterial (IARA). Realizamos ecocardiograma e perfil bioquímico para análise das variáveis e avaliação de lesão de órgãos-alvo. Foram realizadas correlações das variáveis bioquímicas, antropométricas e de lesões em órgãos-alvo com os métodos de avaliação vascular, além da correlação entre os métodos. Observamos uma elevada rigidez arterial tanto pela medida da VOP (12,4 m/s) quanto pelo IARA (0,39), e metade dos pacientes apresentou valores de VOP considerados de pior prognóstico (> 12 m/s). Houve correlação significativa do IARA com a medida da VOP. A distensão da carótida foi menor nos pacientes com diabetes. O principal determinante independente da VOP foi a idade e do IARA os níveis de glicemia. Observou-se correlação significativa e positiva entre a distensão de carótida e o índice de massa de ventrículo esquerdo. Em conclusão, pacientes com hipertensão estágio 3 apresentam alterações importantes das propriedades funcionais de grandes artérias, que são agravadas pelo envelhecimento e pela associação de diabetes, e uma delas está associada à hipertrofia ventricular esquerda presente nestes pacientes.
Functional and structural properties of large arteries have been matter of attention for the better understanding of physiopathological modifications associated to arterial hypertension and aging. Most of these alterations, as arterial stiffness, have been considered independent markers of cardiovascular risk. The evaluation of these properties has not yet been studied in severe hypertensives where the risk for complications is high. The aim of our study was to evaluate, in patients with stage 3 arterial hypertension, vascular changes of large arteries, its major determinants and the correlations with end-organ damage. We evaluated 48 patients (mean age 53,6 ± 8 years; 75% white; 71% women), with stage 3 arterial hypertension, under the same antihypertensive treatment for one month. Carotid parameters (diameter, wall thickness, distension) were evaluated by radiofrequency ultrasound and arterial stiffness by measurement of pulse wave velocity (PWV) and ambulatory arterial stiffness index (AASI). It was performed echocardiogram and biochemical profile to evaluation of other variables and end-organ damage. We did correlations among biochemical, anthropometrical variables and end-organ damage with vascular parameters. We observed increased arterial stiffness measured either by PWV values (12,4 m/s) or AASI (0,39), and half of patients had PWV values considered as a poor prognostic marker (> 12 m/s). It was observed a significant correlation between PWV and AASI. Carotid distension was lower in diabetic patients. The main independent determinant of PWV was age while glycemia was the main determinant of AASI. It was noticed a positive and significative correlation between carotid distension and left ventricle mass index. In conclusion, patients with stage 3 hypertension had important modifications of functional properties of large arteries that are impaired by aging and association of diabetes, and one of them is associated to left ventricle hypertrophy present in these patients

The aim is to demonstrate the utility of magnetic resonance (MR) for identifying subclinical changes associated with the metabolic syndrome (MS) that contribute to increased cardiometabolic risk. The effect of MS on arterial stiffness and tissue iron load were evaluated using MR in subjects with the MS and control subjects. Arterial stiffness was higher in subjects with MS than in those without. The components contributing independently to an increased pulse wave velocity were hypertension and hypertriglyceridemia. Increased iron concentration was significantly detected at the liver and brain in obese subjects. Obesity-associated brain iron overload was correlated with worse cognitive performance. Obesity and insulin resistance were found as the main factors that contribute to tissue iron deposition. In conclusion, this thesis demonstrates the utility of MR to evaluate subclinical risk changes associated with the MS in subjects without diabetes or ischemic disease
L'objectiu general consisteix en posar de manifest la utilitat de la ressonància magnètica (RM) per identificar canvis subclínics associats a la síndrome metabòlica (SM)i que contribueixen a l'increment del risc cardiometabòlic. Es va avaluar l'efecte de la SM sobre la rigidesa arterial i el dipósit de ferro tisular mitjançant RM en individus amb SM i controls. Es va observar un augment de la rigidesa arterial associada a la SM, essent l’hipertensió i hipertrigliceridèmia els principals components desencadenants. També es va observar un augment del dipòsit de ferro hepàtic i cerebral associat a l’obesitat. La sobrecàrrega de ferro cerebral es va correlacionar amb pitjors puntuacions del rendiment cognitiu. Els principals factors precursors de dipòsit de ferro van ser la insulino-resistencia i l'obesitat. En conclusió, es posa de manifest l’utilitat de la RM per avaluar canvis subclínics associats a la SM en individus sense antecedents de diabetis o malaltia vascular isquèmica

Cardiovascular disease varies by ethnicity in the UK. South Asians (SA) have higher coronary heart disease (CHD) and diabetes prevalence, while African-Caribbeans (AfC) have greater stroke, but intriguingly lower CHD rates despite higher blood pressures and diabetes risk than Europeans. Conventional risk factors do not fully explain such differences. This cross-sectional study tested the hypothesis that the hormones, vitamin D measured as 25(OH)D and aldosterone, would be independently associated with intermediate cardiovascular outcome markers in these ethnic groups. Community-dwelling men 40-80 years old (AfC: n=67, 55±10yr; SA: n=68, 55±10yr; European: n=63, 57±8yr) were sampled from Greater Manchester’s multi-ethnic population. The intermediate markers examined were aortic pulse wave velocity (aPWV), left ventricular (LV) mass and function, and carotid intima media thickness (CIMT), measured non-invasively by ultrasound, and hemodynamic profiling methods (the Arteriograph) in the total sample and by magnetic resonance imaging (MRI) in a subsample of 50. Adjusted for age, systolic blood pressure and diabetes, mean(SE) aPWV by the Arteriograph, was 0.5(0.2) m/s higher in SA than AfC and Europeans (p=0.01), which paralleled known cross-ethnic CHD risk differences in the UK. By MRI, aPWV along the descending aorta in SA was 0.7(0.3) and 0.8(0.3) m/s higher than that in AfC and Europeans, but aPWV along the aortic arch was not significantly different. Unlike aldosterone, 25(OH)D was independently and inversely correlated with aPWV (unstandardised B(SE)=-0.013[0.004] m/s, p<0.001), and partly explained the ethnic variation in aPWV. Similar inverse correlations were found between 25(OH)D and LV concentricity measured by echocardiography and MRI. Compared to Europeans, SA and AfC, had 21(3) and 14(3) nmol/L lower mean(SE) 25(OH)D, respectively (p<0.01). Mean(SE) of relative wall thickness, an index of LV concentricity by echocardiography, was 0.05(0.01) higher in SA and AfC than Europeans. Lower 25(OH)D levels were also associated with higher myocardial deformation rates measured by MRI myocardial tagging (n=50), supporting previous animal experimental evidence. A one standard deviation (SD) decrease in 25(OH)D was associated with a 0.38 SD increase in absolute systolic strain rate (p=0.003) and 0.22 SD rise in diastolic strain rate (p=0.04). Right and left CIMT showed different relations with 25(OH)D and aldosterone. Left-right CIMT differences varied by ethnicity and were related to SA ethnicity and aldosterone levels. Two related technical studies investigated the relatively new method of hemodynamic profiling, the Arteriograph, used here. The results suggested a standardisation method of aortic length estimation for purely central aPWV, which significantly improved aPWV agreement between the Arteriograph and MRI (reference method here), and was used for calibrating the Arteriograph aPWV in the above-mentioned results for the total sample. Future well-designed trials are necessary to investigate any cause-effect relationship between vitamin D deficiency and the unfavourable cardiovascular intermediate outcomes found here in a cross-sectional design and multi-ethnic background.